Prevention of Opportunistic Infections (OI) in Patients With HIV Infection

Immunosuppression resulting from HIV places a patient at risk for infection from organisms that are otherwise relatively mildly hazardous and that would normally be cleared by a competent immune system. For many years before the development of effective antiretroviral therapy (ART), these infections inflicted significant morbidity and mortality on patients living with AIDS. They generally include Pneumocystis jiroveci pneumonia (PCP), toxoplasma encephalitis, cryptococcal meningitis, cytomegalovirus (CMV) retinitis, tuberculosis (TB), disseminated Mycobacterium avium complex (MAC), or pneumococcal respiratory disease. ^[1]  

Prevention of opportunistic infections (OI) in patients with HIV has since significantly reduced morbidity and mortality in these patients. HIV-related infections and malignancies escalate in frequency and severity as the absolute CD4 T cell count falls toward 200 cells/μL and below. This risk is more prominent in patients with lower CD4 counts as well as in patients with a longer time spent with more severe immunosuppression; however, it is also seen more severely in patients not on ART. ^[2]  Patients should be aware of their CD4 count and their risk for specific infections and should begin ART.

Opportunistic infections are defined as infections that are either more severe because of HIV-related immunosuppression, or more frequent. ^[3]  As observed in patients with hemophilia who experienced presumed transfusion-related transmission during the 1980s to 1990s, OI generally developed an average of 7 to 10 years after initial HIV infection. ^{[4, 5]}  Survival before widespread effective ART was typically 1 to 2 years after AIDS-defining illness. ^[5]

Besides causing morbidity and mortality alone, OI accelerate the progression of HIV and increase the HIV viral load; ulcerative lesions such as those caused by syphilis can facilitate the spread of HIV. ^{[1, 6, 7, 8]}  Thus, guidelines emphasize ART should be used together with prophylaxis, treatment, secondary prophylaxis, or continuation therapy of OI. Timing of ART warrants thoughtful consideration and knowledge of immunologic, psychosocial, and economic considerations in the specific patient.

Guidelines from the US Centers for Disease Control and Prevention, National Institutes of Health, and the Infectious Diseases Society of America (CDC/NIH/IDSA) emphasize early HIV detection and the supervised administration of ART to maintain cellular immunity before reaching advanced stages of disease. The incidence of OI has fallen dramatically since widespread use of ART began.

Evidence-based changes to the overarching strategy of HIV care have put the most emphasis on restoring immune competence through HIV suppression with ART. One study found significantly reduced incidence of OI after ART initiation, from 15.1 infections per 100 person-years in the 6 months before starting ART to 2.2 infections per 100 person-years after 9 to 15 months of treatment. ^[9]  This is similar to observed CDC data of a reduction in 14 opportunistic infections from 15.1 per 100 person-years to fewer than 2 per 100 person-years. ^[10]  Besides the benefit of reduced mortality, early effective HIV viral suppression is recommended to decrease the rate of HIV transmission to others. ^{[1, 2, 11]}

The recommendations below use evidence-based criteria as published by the joint CDC/NIH/IDSA that summarize the strength of the recommendation and quality of the evidence ^[1] :

Strength of recommendation is as follows:

A: Strong recommendation for the statement

B: Moderate recommendation for the statement

C: Optional recommendation for the statement

Quality of evidence for the recommendation is as follows:

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

II: One or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes

III: Expert opinion

Recommending exposure avoidance is always appropriate, but is usually difficult to implement except in the most compulsive patients. Nevertheless, persons infected with HIV should practice appropriate hygiene and dietary precautions, such as avoiding the following ^{[1, 12]} :

Cat litter and excreta or saliva of farm animals, wild animals, and pets

Animal bites and scratches

Persons with skin infections

Raw meats, eggs, and shellfish; unwashed raw fruits and vegetables

Unpasteurized dairy products

Drinking untreated lake or river water

Human fecal-oral contact

HIV-infected individuals should also limit occupational or recreational exposure to dirt as much as possible in geographic locales with hyperendemic fungal disease (eg, histoplasmosis, coccidioidomycosis, Penicillium marneffei infection). Specially treated water is not helpful. ^[1]

Use of male latex condoms is strongly recommended for preventing transmission of human papillomavirus (HPV) and other sexually transmitted infections. In situations in which male latex condoms cannot be used properly, an FC1 or FC2 female condom should be considered for heterosexual vaginal intercourse (AII recommendation) or male same-sex anal intercourse (BIII recommendation). ^[1]

Drug, alcohol, and tobacco abuse prevention and therapy should be part of any HIV management program. Many patients with HIV have suffered trauma, placing them at higher risk for poor adherence to preventive and therapeutic interventions. All programs should incorporate principles of trauma-informed care in optimally assisting patients to better health. ^{[13, 14]}

Despite increasingly widespread and targeted HIV screening, many HIV infections continue to be diagnosed late and after OI have already developed. ^[15]  Favorably for these patients, initiating ART in patients with CD4 counts below 350 cells/uL results in a significant decline in the risk for AIDS-related morbidity and mortality. ^{[16, 17, 18, 19, 20, 21]}  

For most patients, ART should be initiated shortly after diagnosis, regardless of CD4 count or viral load ^{[22, 23, 24, 25]} ; however, ART should be initiated within 2 weeks for patients presenting with OI. ^{[1, 22, 23]}  When compared with a deferred (median, 45 days) ART initiation strategy, an early (mean, 12 days) ART initiation strategy for patients presenting with AIDS (median CD4, 29) plus an OI was associated with less AIDS progression and death without increased adverse events or loss of virologic response. ^[16]  

Early ART is indicated for patients presenting with PCP, toxoplasmosis encephalitis, and pulmonary TB; however, early ART initiation is controversial in cases of a new HIV diagnosis with comorbid cryptococcal meningitis or tuberculous meningitis (TB meningitis). ^{[26, 27, 28, 29]}  A 5-week deferral of ART initiation in cases of cryptococcal meningitis was associated with improved 6-month survival (hazard ratio, 1.73 [1.06 - 2.82]). ^[29]  A small study in a resource-limited area of Zimbabwe found that early ART initiation (within 72 hours of diagnosis) was associated with a 3 times higher risk for mortality compared with a 10-week deferral (hazard ratio, 2.85 [1.1 - 7.23]). ^[28]  Patients with CD4 counts of fewer than 50 cells/μL at presentation should be considered for serum cryptococcal antigen testing, and, if diagnosed with cryptococcal meningitis, it may be prudent to delay ART for at least 2 weeks and possibly up to 10 weeks into cryptococcal therapy. ^{[1, 26]}

Regarding comorbid TB meningitis, a randomized trial of patients with advanced AIDS in Vietnam showed no survival benefit to addition of early ART (within 7 days) during treatment of TB meningitis compared with deferred ART (after 8 weeks). Early ART was associated with more frequent and severe adverse events (86% vs 75%), however. ^{[1, 30]}

It should be identified that many newly diagnosed patients have significant psychiatric, social, and economic problems, as well as major medical comorbidities and drug abuse. The healthcare team must address and control these issues if prophylaxis and treatment are to be successful; this requires motivation and cooperation on the part of the patient.

The following CD4 counts are useful landmarks for initiation of antimicrobial prophylaxis ^{[1, 2]} :

Less than 250 cells/μL - Coccidioidomycosis prophylaxis if seropositive in high-risk area

Less than 200 cells/μL - PCP prophylaxis

Less than 150 cells/μL - Histoplasmosis prophylaxis if exposure to hyperendemic areas

Less than 100 cells/μL - Toxoplasmosis prophylaxis (if seropositive)

Less than 100 cells/uL - Cryptococcosis preemptive therapy if antigen-positive

Less than 100 cells/μL - Penicilliosis prophylaxis if living in high-risk area

Less than 50 cells/μL - M avium complex (MAC) infection prophylaxis unless ART is immediately initiated ^[1]

Prior to initiation of prophylaxis, the clinician should attempt to clinically exclude active disease, as the prophylactic regimen may not sufficiently treat an active infection or may even mask signs of infection. In most cases, obtaining a thorough history and conducting an examination with symptom-targeted laboratory and radiologic tests are enough to exclude active P carinii pneumonia (PCP), M avium complex (MAC) infection, and tuberculosis. Increasingly, serum cryptococcal antigen testing is used to screen at-risk patients for early disease, particularly in Africa. ^{[31, 32]}

Adverse drug reactions to prophylactic therapy are common and should be expected. Patients should completely understand the purpose of the prophylaxis, the possible adverse effects, and what to do if they occur. Typical toxicities include the following:

Trimethoprim-sulfamethoxazole – Rash, neutropenia, elevated creatinine

Dapsone - Rash; anemia; methemoglobinemia, especially if G-6-PD deficient

Azithromycin and clarithromycin - Gastrointestinal distress (abdominal pain and diarrhea), QT prolongation (clarithromycin)

Pyrimethamine - Leukopenia

Itraconazole - Hepatitis (hepatitis is less likely with fluconazole), QT prolongation

Atovaquone - Headache, nausea, diarrhea, rash, transaminase elevation

As patients live longer with long-term immunosuppression and control of the HIV virus, they often accumulate multiple comorbid conditions associated with early aging. These include renal and hepatic disease, hyperlipidemia, lung disease, and cardiovascular disease. Drug-drug interactions with antiretroviral therapy and prophylactic drugs is inevitable. Automated drug interaction screens can alert the physician to unanticipated potential interactions of variable significance.

On the patient's first visit, serologies for syphilis; hepatitis A, B, and C; and toxoplasmosis should be obtained. Although the incidence of CMV disease, including retinopathy, has declined significantly, it is recommended that patients with HIV who are not at high risk for CMV infection (ie, men who have sex with men, people who intravenously inject drugs, or patients who are exposed to children in daycare centers) be screened to confirm that they are CMV-negative (BIII recommendation). ^[33]  Such HIV-positive, CMV-negative persons would be instructed to limit exposure to CMV by using latex condoms and other barrier precautions (AII recommendation), be informed of the risk for acquisition in daycare facilities (BII recommendation), and be instructed to accept only CMV-seronegative or leukocyte-reduced blood products in nonemergent situations (BIII recommendation). ^[1]

Urine chlamydial and gonorrheal nucleic acid amplification testing should be performed in all patients with newly diagnosed HIV infection. Similarly, patients who participate in oral or anal receptive intercourse should undergo site directed chlamydial and gonorrheal nucleic acid amplification testing. Women should be evaluated for trichomoniasis. A purified-protein derivative (PPD) skin test should be placed unless a previous positive result for TB has been documented. An interferon-gamma release assay may be sufficiently sensitive for 1-step testing, but false-negative test results are common in advanced immunodeficiency. ^[1]

Pneumococcal PCV13 vaccine should be administered on the first visit, and on subsequent visits, vaccines for hepatitis A, hepatitis B, diphtheria-tetanus, and influenza should be administered as indicated by serology results, history, and season, respectively. Patients should be given the PPV23 vaccine at least 8 weeks after the PCV13, if it has not already been administered. ^[1]  The 9-valent recombinant HPV vaccine should be given to all patients 11 to 26 years of age, or up to 45 years of age with shared decision making. ^[1]  All live vaccines should be avoided in HIV-infected patients, with the exception of measles and varicella vaccines in immunocompetent patients (in general, CD4 count >200 cells/μL). ^[1]  The meningococcal ACWY vaccine should be administered routinely. ^[1]  Meningococcal B vaccine may be given to adolescents and young adults based on individual clinical decision. ^[1]  Haemophilus influenzae B vaccine should be administered to adults and adolescents with HIV for such indications as asplenia, hematopoietic stem cell transplant, and others. ^[1]  

Once initiated, prophylaxis should be ideally accompanied by education from a trained educator and such teaching should be documented; the same educator should reinforce ART. At each visit, patients should bring their prescription bottles and explain the purpose of their medications. Failure to give correct answers or to bring bottles warrants a return visit to the educator.

As a patient improves, CD4 counts rise, and the immune system is reconstituted, prophylaxis can often be terminated. The containers of terminated drugs may need to be removed from the patient’s possession, and repeated calls and email messages may need to be sent to the pharmacy to ensure delivery of the drugs to the patient stops. Continuing unnecessary medication could be a significant problem, especially with electronic prescribing, unless specific efforts are made to stop the drug.

After ART is initiated and HIV viremia is suppressed, PCP and toxoplasmosis prophylaxis should  continue until the CD4 count exceeds 200 cells/μL for 3 months (AI recommendation) or 100 to 200 cells/uL with negative HIV viral load for 6 months (BII recommendation). Histoplasmosis prophylaxis can be discontinued when the CD4 count has exceeded 150 cells/μL for 6 months (BIII recommendation); coccidioidomycosis prophylaxis can be stopped when CD4 counts exceed 250 cells/μL for 6 months (CIII recommendation); and penicilliosis prophylaxis can be discontinued when CD4 counts exceed 100 cells/μL for 6 months (BII recommendation). ^[1]

P jiroveci pneumonia (PCP)

Indications for PCP prophylaxis include a CD4 count of fewer than 200 cells/μL (AI recommendation) or less than 14% of lymphocytes (BII recommendation). The preferred regimen is trimethoprim-sulfamethoxazole 1 double-strength tablet orally daily (AI) or 1 double-strength tablet orally 3 times weekly(BI). Alternatives include dapsone 100 mg orally daily (BI), aerosolized pentamidine 300 mg administered via the Respirgard II nebulizer monthly (BI), or atovaquone suspension 750 mg (5 mL) orally twice daily)(BI). ^[1]

Latent Mycobacterium tuberculosis infection (LTBI) and exposure

Tuberculosis (TB) is both the leading cause of death from infectious disease globally and the leading cause of morbidity and mortality among people living with HIV. ^[1]  Screening for TB in the HIV-infected population has been suboptimal, with only 47% to 65% of patients completing screening. The most common predisposition for TB is birth or residence outside of the United States. ^[1]  All persons with HIV should be tested for LTBI regardless of their epidemiologic risk for TB exposure (AII recommendation). ^[1]  All newly-diagnosed patients with HIV infection should be screened with a tuberculin skin test (TST) or interferon-gamma release assay (IGRA), and re-screened once the CD4 count rises to 200 if initially less. ^{[1, 34]}

Treatment for LTBI is indicated for all patients with a history of a positive TST result of 5 mm or greater or an IGRA who have not previously received therapy (AI recommendation). Patients with HIV who are close contacts of a person with infectious TB yet show no signs themselves of active TB, should be administered LTBI treatment regardless of screening results (AII recommendation). ^[1]  This appears particularly critical for HIV-seropositive children not on ART, as a Cochrane review of a South African study has shown a 69% reduction in the risk for active TB and a 54% reduction in death. ^[34]  An Ethiopian study showed improved outcomes in adults on combined ART and LTBI therapy. ^[35]

Active TB should be excluded by lack of symptoms and negative chest radiograph before prophylactic regimens are started. Active TB may be more likely in a patient with previous active TB (treated or untreated) than in a patient without a history of TB.

Isoniazid monotherapy for 9 months remains the preferred therapy, with proven efficacy, tolerability, and infrequent severe toxicity as a monotherapy (AI recommendation). ^{[1, 23]}  Nine months was shown to be superior to 6 months in patients with HIV, with peak benefit around 9 months. ^[36]  A significant disadvantage of a 9-month regimen is that compared with other shorter regimens, patients are more likely to not complete treatment. Possible alternative therapy (but not preferred) includes weight-based rifapentine once weekly, plus isoniazid once weekly, plus pyridoxine once weekly for 12 weeks (B recommendation). ^[1]

M avium complex (MAC) infection

Primary prophylaxis for MAC in people living with HIV infection who immediately initiate ART is no longer recommended, regardless of CD4 count (AII recommendation). ^[1]  This is based on multiple randomized placebo-controlled trials and observational data that found no increased risk of developing MAC in patients taking suppressive ART with or without addition of azithromycin. ^{[37, 38, 39]}

Patients who expect a delayed initiation of ART and who have a CD4 count of fewer than 50 cells/μL should be given azithromycin 1200 mg orally weekly after ruling out disseminated MAC infection on clinical assessment (AI recommendation). Alternatives include clarithromycin 500 mg orally twice daily (AI recommendation) or rifabutin 300 mg orally daily with drug dose modifications noted above (BI recommendation).

Toxoplasma gondii infection

Patients with a CD4 count below 100 cells/μL who are not previously known to be seronegative for toxoplasma immunoglobulin G (IgG) should receive prophylaxis for toxoplasmosis. Trimethoprim-sulfamethoxazole, 1 double-strength tablet orally once daily is preferred (AII recommendation). Dapsone alone is ineffective against toxoplasmosis. Therefore, dapsone 50 mg orally daily plus pyrimethamine 50 mg orally weekly plus leucovorin 25 mg orally weekly is appropriate for both PCP and toxoplasmosis (BI recommendation). Alternatively, atovaquone with or without pyrimethamine/leucovorin can be considered. ^[1]

Varicella-zoster virus infection

HIV-infected patients should generally avoid close contact with persons with zoster or chickenpox.

Live-virus vaccines should not be administered to persons with HIV and CD4 counts lower than 200 cells/µL (AIII recommendation). Guidelines continue to recommend varicella immune globulin (AIII recommendation) for postexposure prophylaxis, and to consider a 7- to 10-day course of acyclovir or valacyclovir in this situation (BIII recommendation). ^[1]

There are limited data for use of the recombinant zoster vaccine (RZV) in patients with HIV, although the CDC’s Advisory Committee on Immunization Practices has not recommended use in this manner. A phase 1/2 randomized placebo-controlled trial of 123 patients with HIV who were given RZV according to the FDA-approved schedule for persons without HIV showed increased humoral and cell-mediated immunity against VZV. ^{[1, 40]}  This included patients with CD4 counts of less than 200 cells/mm³. No vaccine-related severe adverse events occurred, though side effects (injection site pain, fatigue, myalgia, headache) were common. ^[40]

Given the lifetime risk for zoster and the safe profile of the vaccine, experts recommend administration of RZV to persons with HIV who are 50 years of age or older according to the FDA-approved schedule for persons without HIV (IM dose at 0 and 2 months) (AIII recommendation). ^[1]

Syphilis

Patients exposed to a sex partner with a diagnosis of primary, secondary, or early latent syphilis within the past 90 days should receive benzathine penicillin G 2.4 million units intramuscularly as a single dose (AII recommendation). ^[1]

Histoplasmosis

Patients with a CD4 count of less than 150 cells/μL at high risk for exposure or who live in a hyperendemic area should receive itraconazole 200 mg PO daily (BI recommendation). ^[1]

Coccidioidomycosis

Patients with a new positive immunoglobulin M (IgM) or IgG serologic test result who live in endemic areas and have a CD4 count of less than 250 cells/μL should receive fluconazole 400 mg PO daily (BIII recommendation). ^[1]

Penicilliosis (recently renamed talaromycosis)

Patients with a CD4 count of less than 100 cells/μL living or staying in rural endemic areas of Southeast Asia should receive itraconazole 200 mg PO daily (BI recommendation). ^[1]

Cryptococcal disease

While US guidelines do not recommend screening or prophylaxis of cryptococcal disease, the World Health Organization recommends the following based on high prevalence and mortality in Africa: screening adult and adolescent patients with a CD4 count < 100 cells/µL not suspected of meningitis for cryptococcal antigen followed by preemptive therapy (short-course 1 week amphotericin B deoxycholate plus flucytosine followed by 1 week of high-dose fluconazole before ART (strong recommendation; moderate-certainty evidence). 

Such therapy "should be considered" in antigen-positive adults and adolescents with a CD4 count of fewer than 200 cells/µL (conditional recommendation; moderate-certainty evidence). In the absence of available antigen screening, fluconazole prophylaxis (200 mg/day) should be given to adults and adolescents with HIV infection who have a CD4 count below 100 cells/µL (strong recommendation, moderate-certainty evidence) and "may be considered" in patients with a CD4 count of 100 to 200 cells/µL (conditional recommendation; moderate-certainty evidence). This guideline considers it "a good practice principal" to perform a lumbar puncture with opening pressure in all patients who are cryptococcal antigen positive.

All HIV-positive adolescents and adults who have never had a pneumococcal vaccine should receive a single dose of PCV13 at presentation (AI recommendation). If CD4 cell count is higher than 200 cells/µL, they should receive a 23 valent polysaccharide vaccine (PPV23) at least 8 weeks later (AII recommendation). Those with a CD4 cell count of less than 200 cells/µL should preferably wait until the CD4 count is higher than 200 cells/µL with antiretroviral therapy (ART) before receiving the PPV23 (BIII recommendation). PCV13 should be given to patients who have previously received PV23 (AII recommendation) more than a year prior (AII recommendation). ^[1]

Other recommended vaccinations are as follows:

Hepatitis B virus infection - All susceptible (anti-HBc-negative) patients should receive the 3-dose hepatitis B vaccine (AII recommendation)

Influenza virus infection - Annual seasonal influenza vaccination is recommended by ACIP for all patients with HIV over the age of 6 months. Live attenuated intranasal vaccine (LIAV) should not be used in patients with HIV. While there is no recommendation for high dose influenza vaccination, a randomized trial of high vs standard dose in HIV-infected adults showed increased seroprotection rates against H1N1 (96 vs 87%) and influenza B (91 vs 80%), but not H3N2 (96 vs 92%). ^[41]

Hepatitis A virus infection - All susceptible (anti-HAV-negative) patients should receive the 2-dose hepatitis A vaccine (AII recommendation)

The 9-valent recombinant human papillomavirus (HPV) vaccine (0.5 mL at 0, 1-2, and 6 months) is recommended in HIV-positive males and females aged 11-26 years (AIII recommendation), even if they have received previous bivalent or quadrivalent vaccines (CIII recommendation) plus ages 27-45 years based on shared decision making. ^[1]

Meningococcal ACWY - Two doses 2 months apart and every 5 years

Tetanus, diphtheria, and pertussis - Tdap if not previously vaccinated, followed by Td booster every 10 years

Measles, mumps, rubella - Two-dose series at least 1 month apart in adults and adolescents without historical or serological evidence of immunity and a CD4 count >200 cells/µL

Varicella - Two-dose series at least 3 months apart in adults and adolescents without historical or serological evidence of immunity and a CD4 count >200 cells/µL

Fungal or yeast infections

According to current NIH guidelines, Cryptococcus neoformans and Candida infections do not warrant primary prophylaxis. ^[24]  In the case of Cryptococcus infection, primary prophylaxis has not been shown effective in Thailand. ^[42]  New WHO guidelines recommend cryptococcal antigen testing and preemptive therapy in antigen-positive patients with a CD4 count < 100 cells/uL in Africa and other areas of high prevalence. Prolonged suppressive therapy for Candida is not recommended owing to risk of resistance. However, if necessary because of frequent recurrence or severe disease, fluconazole 100 mg PO thrice weekly for thrush (BI recommendation), fluconazole 100-200 mg daily (esophagitis) (BI), or fluconazole 150 mg PO once weekly (vaginitis) (CII recommendation) are the first recommended drugs. ^[24]

Fortunately, aspergillosis and phycomycosis (mucormycosis) are rare in individuals infected with HIV. These infections should be considered in patients with invasive sinusitis and focal pulmonary lesions but do not warrant prophylaxis.

Travelers to malaria-prone areas should have malaria prophylaxis, and those who live in such areas should practice preventative measures, such as the use of treated mosquito netting.

Bacterial infections

Prophylaxis (primary or secondary) for the following community-acquired and healthcare-associated infections is seldom indicated, although these infections are not uncommon in patients infected with HIV:

Methicillin-resistant Staphylococcus aureus folliculitis and cellulitis

Streptococcal cellulitis

Campylobacter enteritis

Salmonella enteritis and bacteremia

Shigella infection, Mycoplasma infection

Rhodococcus pneumonia

Legionella infection

Bartonella dermatitis

Gram-negative enteric urinary tract and pulmonary infections

Traveler's diarrhea

Persons infected with HIV are at high risk for sexually transmitted diseases such as syphilis, chlamydia, and gonorrhea. These should be reported to authorities and treated with documented cure and provision of counseling to avoid reinfection. Individuals exposed to a sex partner with a diagnosis of primary, secondary, or tertiary syphilis should be treated prophylactically with benzathine penicillin G 2.4 million units intramuscularly one time (AII recommendation).

Nocardia infection is rare in even late stages of AIDS, probably because it is inhibited serendipitously by P carinii pneumonia (PCP) prophylaxis with trimethoprim-sulfamethoxazole.

Protozoal and helminthic infections

Patients infected with HIV are at risk for infections with Cryptosporidium species, Giardia species, Isospora species, Cyclosporaspecies, and Microsporidia species, as well as Entamoeba species and Strongyloidiasis species in some locales and with exposure to animals, especially animals with diarrhea. Neither primary nor secondary prophylaxis is indicated. Concomitant malaria and HIV disease is a major problem in Africa, but trimethoprim-sulfamethoxazole may have some prophylactic benefit ^[24]

Patients with risk factors for Chagas disease and who are seropositive for Trypanosoma cruzi who have not been previously treated and do not have advanced cardiomyopathy can be considered for a course of either benznidazole or nifurtimox, but efficacy is suboptimal (CIII recommendation), while prompt ART therapy may prevent reactivation of parasitic disease (BIII recommendation) ^[24] .

Other viral infections

Recurrent genital and, occasionally, oral herpes simplex infections, zoster, molluscum contagiosum, and human papillomavirusinfections are common. Primary infections are best avoided. Recurrent herpes simplex and zoster may be prevented with acyclovir 400 mg twice daily, continued indefinitely (AI recommendation). The efficacy of the 9-valent recombinant human papillomavirus (HPV) vaccine to prevent warts and neoplasia is unknown in adult patients infected with HIV, but it is recommended for men and women aged 11-26 years and ages 27-45 with shared decision making (see above) ^[24] . Progressive multifocal leukoencephalopathy (JC virus) is not susceptible to prophylaxis, and no therapy other than immuno-reconstitution is recommended ^[24] . HHV-8 infection is not specifically treated, but HIV viral therapy plus chemotherapy is given for Kaposi sarcoma.

Secondary prophylaxis (called maintenance therapy in the NIH/CDC guidelines) consists of therapy given to prevent relapse of known and appropriately treated OI that have occurred before effective antiretroviral therapy (ART). For most of these infections, the initial treatment is much more intensive and may last for 2 to 4 weeks, followed by the secondary prophylaxis regimen. This is particularly noteworthy for cryptococcal meningitis, which must be treated initially with amphotericin and flucytosine.

For P carinii pneumonia (PCP), the recommended secondary prophylaxis is trimethoprim-sulfamethoxazole, a double-strength tablet orally daily (AI recommendation), until the CD4 count exceeds 200 cells/μL for 3 months (BII recommendation).

For toxoplasmosis, the following is recommended: sulfadiazine 500 to 1000 mg orally 4 times daily plus pyrimethamine 25 to 50 mg orally daily and leucovorin 10 to 25 mg orally daily (AI recommendation) until the CD4 count exceeds 200 cells/μL for 6 months (AIII recommendation). An additional agent must be added to prevent PCP.

For TB, it is important to collect specimens for culture and probes before therapy is started. Initial-phase therapy consists of 2 months of isoniazid, rifampin or rifabutin, pyrazinamide, and ethambutol daily or 5 to 7 times per week under direct observation (AI recommendation). The continuation phase, after ensuring drug susceptibility and repeat cultures, consists of daily isoniazid and rifampin or rifabutin for 6 months for pulmonary TB, 9 months for pulmonary TB in which cultures remained positive after the initial 2 months of therapy, 9 to 12 months for extrapulmonary TB with CNS involvement, 6 to 9 months for extrapulmonary TB with bone or joint involvement, and 6 months for disease limited to other sites (all BII recommendations).

For M avium complex (MAC) infection, the following is recommended: clarithromycin 500 mg orally twice daily plus ethambutol 15 mg/kg orally daily with or without rifabutin 300 mg orally daily for 12 months until patients have no signs or symptoms of MAC disease and until the CD4 count is greater than 100 cells/μL for 6 months (AII recommendation).

For CMV retinitis, maintenance therapy for immediate vision-threatening lesions close to the fovea consists of intravitreal injections of ganciclovir (2 mg/injection) or foscarnet (2.4 mg/injection) for 1 to 4 doses over 7 to 10 days (AIII recommendation) plus valganciclovir 900 mg PO BID for 14 to 21 days, then 900 mg PO once daily (AI recommendation). Therapy for peripheral lesions consists of systemic antiviral therapy (various regimens of ganciclovir, valganciclovir, foscarnet, and cidofovir) (AII recommendation). Maintenance therapy for central or peripheral lesions should be continued for at least 3 to 6 months and until lesions are inactive and the CD4 count has risen to more than 100 cells/μL (AII recommendation). Maintenance therapy should be stopped only after ophthalmological consultation. Quarterly retinal examinations are indicated during the follow-up period after stopping therapy (AIII recommendation). The duration of initial therapy for CMV gastrointestinal disease is 21 to 42 days or until signs and symptoms have resolved (CII recommendation). The use of maintenance therapy for CMV gastrointestinal, pulmonary, or neurological disease is not established but should probably be individualized, especially during relapses or immune reconstitution reactions.

For cryptococcal meningitis, after initial liposomal amphotericin and flucytosine therapy for at least 2 weeks, give fluconazole 400 mg orally or intravenously daily as "consolidation" therapy (AI recommendation). This should be followed by "maintenance" therapy with fluconazole 200 mg PO daily for at least 1 year (AI recommendation) and until the CD4 count exceeds 100 cells/μL for 3 months (BII recommendation).

Similarly, initial treatment for moderate to severely disseminated histoplasmosis consists of liposomal amphotericin B for induction of at least 2 weeks, followed by maintenance therapy consisting of itraconazole 200 mg TID for 3 days and then 200 mg BID for 12 months (AII recommendation).

Coccidioidomycosis infections are usually treated with fluconazole for mild disease or amphotericin for severe disease, followed by long-term suppressive therapy with oral fluconazole 400 mg daily or oral itraconazole 200 mg PO BID (AII recommendation).

For mucocutaneous and esophageal Candida infection, long-term suppressive therapy is usually not indicated or necessary, especially if the CD4 count rises above 200 cells/μL (BIII recommendation). Frequent or long-term therapy can result in resistance. If the decision is made to use suppressive therapy, use fluconazole 100 mg orally daily or 3 times weekly for oropharyngeal disease (BI recommendation), fluconazole 100 mg to 200 mg orally daily for esophageal disease (BI recommendation), or fluconazole 150 mg orally weekly for vulvovaginal disease (BII recommendation).

For recurrent herpes simplex infection, valacyclovir 500 mg PO BID or acyclovir 400 mg PO daily is recommended as long-term suppression (AI recommendation). The ongoing need for continued suppression should be evaluated yearly as the CD4 cell count rises with ART.

For recurrent methicillin-resistant S aureus (MRSA) infection, the recommendation is mupirocin 2% nasal ointment to each nostril twice daily for 5 days if colonization is documented. Long-term efficacy is uncertain, and resistance may develop. Germicidal soaps have been recommended for perineal colonization, but little evidence suggests efficacy. Hygienic measures should be emphasized for this epidemic problem.