Opportunistic Infections in AIDS

Yasir Ahmed

Sean Cook

Helmut Albrecht

An opportunistic infection (OI) is an infection caused by pathogens that usually do not cause disease in a host with a healthy immune response but may have an “opportunity” to do so in patients with a compromised immune system. In patients with HIV infection, OIs are defined as infections that are either more frequent or more severe due to advancing immunosuppression.

In the early 1990s, the introduction of prophylactic medications and better treatment strategies for the management of acute OIs led to improved survival in patients with HIV. In the mid-1990s, the introduction and widespread use of potent antiretroviral therapy (ART) regimens led to a profound reduction of OI-related mortality.¹ Despite the availability of potent ART, however, OIs continue to be a leading cause of both morbidity and mortality in patients with HIV and AIDS.²

The degree of immunosuppression, as measured by CD4 cell counts, in most instances correlates with the risk of specific OIs (Table 2-1).

While the list can be used for risk stratification, it should be noted that CD4 cell counts are unreliable in acutely ill patients or in patients with other immunocompromising conditions (such as end-stage renal disease or postsplenectomy). The following lists pertinent features of common or important OIs. Additional information is available elsewhere2 and treatment options are summarized in Table 2-2.

PNEUMOCYSTIS JIROVECII PNEUMONIA

Pulmonary infection with the fungal pathogen Pneumocystis jirovecii causes Pneumocystis jirovecii pneumonia (PJP or PCP). PCP clinically presents as a subacute process with progressive dyspnea, fever, and nonproductive cough that has been worsening over several weeks prior to presentation.

Initial radiography may not show disease, but patients with severe illness typically present with bilateral interstitial infiltrates with perihilar distribution. A significant elevation of the serum lactate dehydrogenase (LDH) is often present, but this finding is nonspecific. Hypoxemia may be present and may become severe. HIV-infected adults should receive primary PCP prophylaxis if they have a CD4+ count of <200 cells/µL, a CD4+ cell percentage of <14%, or a history of an AIDS-defining illness or oropharyngeal candidiasis. Trimethoprim-sulfamethoxazole one double-strength tablet daily is the preferred agent, but dapsone, atovaquone, and aerosolized pentamidine constitute alternative options.²

TOXOPLASMOSIS ENCEPHALITIS

Toxoplasmosis encephalitis (TE) caused by Toxoplasma gondii is almost exclusively due to reactivation of preexisting disease. Initial presentation typically involves

headache, confusion, and focal neurologic findings. Contrast computed tomography (CT) imaging of the brain usually shows a single or multiple ring-enhancing lesions. The empiric diagnosis is confirmed through clinical and radiographic improvement following treatment initiation.

Table 2-1 Risk Stratification for Specific Opportunistic Infections by CD4 Cell Count

CD4 Count	Opportunistic Infection(s)
>200	Tuberculosis, KS
<200	Tuberculosis, KS, PCP, disseminated histoplasmosis
<100	Toxoplasma gondii encephalitis, cryptococcal meningitis, cryptosporidiosis, microsporidiosis
<50	DMAC, CMV infection, PML

Table 2-2 Drug Therapy for Treatment and Chronic Maintenance Therapy of AIDS-Associated OIs in Adults and Adolescents

OI	Preferred Therapy, Duration of Therapy, Chronic Maintenance	Alternative Therapy
PCP	Preferred treatment for moderate to severe PCP Trimethoprim-sulfa-methoxazole (TMP-SMX) (15-20-mg TMP and 75-100-mg SMX)/kg/day IV administered q6h or q8h (AI), may switch to PO after clinical improvement (AI) Indications for corticosteroids *(AI)* PaO₂ < 70 mm Hg at room air or alveolar-arterial O₂ gradient >35 mm Hg Dose of prednisone: Days 1-5: 40 mg PO b.i.d. Days 6-10 40 mg PO q.d. Days 11-21: 20 mg PO q.d.	Alternative therapy for moderate to severe PCP Pentamidine 4 mg/kg IV daily infused over ≥60 minutes (AI), certain specialists reduce dose to 3 mg/kg IV daily because of toxicities (BI); or Primaquine 15-30 mg (base) PO daily plus clindamycin 600-900 mg IV q6h to q8h or clindamycin 300-450 mg PO q6h to q8h (AI)
	Preferred treatment for mild to moderate PCP Trimethoprim-sulfamethoxazole (TMP-SMX) DS 2 tablets PO t.i.d. (AI) Duration of therapy for PCP is 21 days (AII).	Alternative therapy for mild to moderate PCP Dapsone 100 mg PO daily and TMP 15 mg/kg/day PO (three divided doses) (BI); or Primaquine 15-30 mg (base) PO daily plus clindamycin 300-450 mg q6-8h (BI); or Atovaquone 750 mg b.i.d. PO (BI)
Toxoplasma gondii encephalitis	Preferred therapy Pyrimethamine 200 mg PO × 1, then 50-75 mg PO daily plus sulfadiazine 1,000-1,500 mg PO q6h plus leucovorin 10-25 mg PO daily (AI) Duration for acute therapy At least 6 weeks (BII); longer duration if clinical or radiologic disease is extensive or response is incomplete at 6 weeks Adjunctive corticosteroids (e.g., dexamethasone) should be administered when clinically indicated.	Alternative therapy regimens Pyrimethamine (leucovorin)^* plus clindamycin 600 mg IV or PO (AI); or TMP-SMX (5 mg/kg TMP and 25 mg/kg SMX) IV or PO b.i.d. (BI); or Atovaquone 1,500 mg PO b.i.d. with food (or nutritional supplement) plus pyrimethamine (leucovorin)^*(BII); or Atovaquone 1,500 mg PO b.i.d. plus sulfadiazine 1,000-1,500 mg PO q6h (BII); or Atovaquone 1,500 mg b.i.d. PO (BII); or Pyrimethamine (leucovorin)^* plus azithromycin 900-1,200 mg PO daily (BII)
Cryptosporidiosis	Preferred therapy	Alternative therapy for cryptosporidiosis
	Initiate or optimize ART for immune restoration (AII) Symptomatic treatment of diarrhea (AII) Aggressive oral or IV rehydration and replacement of electrolyte loss (AIII)	A trial of nitazoxanide 500-1,000 mg PO b.i.d. with food for 14 days (CIII) + optimized ART, symptomatic treatment and rehydration and electrolyte replacement
Microsporidiosis	Initiate or optimize ART; immune restoration to CD4+ count >100 cells/µL is associated with resolution of symptoms of enteric microsporidiosis (AII).
M. tuberculosis (TB)	Empiric treatment should be initiated and continued in HIV-infected persons in whom TB is suspected until all diagnostic workup is complete (AII).
	Treatment of drug-susceptible active TB disease Initial phase (2 months) (AI) Isoniazid (INH)^† + [rifampin (RIF) or rifabutin (RFB)] + pyrazinamide (PZA) + ethambutol (EMB); if drug susceptibility report shows sensitivity to INH and RIF and PZA, then EMB may be discontinued before 2 months of treatment is completed (AI) Continuation phase INH + (RIF or RFB) daily or t.i.w. (AIII) or biw (if CD4+ count >100/µL) (CIII) Duration of therapy: Pulmonary TB—6 months (AI) Pulmonary TB with cavitary lung lesions and (+) culture after 2 months of TB treatment (AII)—9 months Extrapulmonary TB with CNS, bone, or joint infections—9 to 12 months (AII) Directly observed therapy (DOT) is recommended for all HIV patients under-going treatment for active TB (AII).	Treatment for drug-resistant active TB Resistant to INH Discontinue INH (and streptomycin, if used) (RIF or RFB) + EMB + PZA for 6 months (BII); or (RIF or RFB) + EMB for 12 months (preferably with PZA during at least the first 2 months) (BII) A fluoroquinolone may strengthen the regimen for patients with extensive disease (CIII). Therapy should be individualized based on resistance pattern and with close consultation with experienced specialist (AIII).
DMAC disease	Preferred therapy for DMAC At least two drugs as initial therapy with Clarithromycin 500 mg PO b.i.d. (AI) + ethambutol 15 mg/kg PO daily (AI)	Alternative therapy for DMAC Azithromycin 500-600 mg + ethambutol 15 mg/kg PO daily (AII)
	Addition of rifabutin may also be considered: Rifabutin 300 mg PO daily (dosage adjustment may be necessary based on drug-drug interactions) (CI)	Addition of a third or fourth drug should be considered for patients with advanced immunosup-pression (CD4+ count <50 cells/µL), high mycobacterial loads (>2 log CFU/mL of blood), or in the absence of effective ART (CIII). Other drugs used are amikacin, streptomycin, ciprofloxacin, levofloxacin, and moxifloxacin.
Cryptococcal meningitis	Preferred induction therapy	Alternative induction therapy
	Amphotericin B deoxycholate 0.7 mg/kg IV daily plus flucytosine 100 mg/kg PO daily in four divided doses for at least 2 weeks (AI); or Lipid formulation amphotericin B 4-6 mg/kg IV daily (consider for persons who have renal dysfunction on therapy or have high likelihood of renal failure) plus flucytosine 100 mg/kg PO daily in four divided doses for at least 2 weeks (AII)	Amphotericin B (deoxycholate or lipid formulation, dose as preferred therapy) plus fluconazole 400 mg PO or IV daily (BII) Amphotericin B (deoxycholate or lipid formulation, dose as preferred therapy) alone (BII) Fluconazole 400-800 mg/day (PO or IV) plus flucytosine 100 mg/kg PO daily in four divided doses for 4-6 weeks (CII)—for persons unable to tolerate or unresponsive to amphotericin B
	Preferred consolidation therapy Fluconazole 400 mg PO daily for 8 weeks (AI)	Alternative consolidation therapy Itraconazole 200 mg PO b.i.d. for 8 weeks (BI), or until CD4+ count ≥200 cells/µL for >6 months as a result of ART (BII)
	Preferred maintenance therapy Fluconazole 200 mg PO daily (AI) lifelong or until CD4+ count ≥200 cells/µL for >6 months as a result of ART (BII)	Alternative maintenance therapy Itraconazole 200 mg PO daily.
Histoplasma capsulatum infections	Preferred therapy for moderately severe to severe disseminated disease Induction therapy (for 2 weeks or until clinically improved) Liposomal amphotericin B at 3 mg/kg IV daily (AI)	Alternative therapy for moderately severe to severe disseminated disease Induction therapy (for 2 weeks or until clinically improved) Amphotericin B deoxycholate 0.7 mg/kg IV daily (BI) Amphotericin B lipid complex 5 mg/kg IV daily (CIII)
	Maintenance therapy	Maintenance therapy same as “preferred therapy”
	Itraconazole 200 mg PO t.i.d. for 3 days, then b.i.d. (AII) Itraconazole levels should be obtained in all patients to ensure adequate absorption (AIII)
	Preferred therapy for less severe disseminated disease Induction and maintenance therapy Itraconazole 200 mg PO t.i.d. for 3 days, then 200 mg PO b.i.d. (AII) Duration of therapy: at least 12 months
CMV disease	Preferred therapy for CMV retinitis For immediate sight-threatening lesions Ganciclovir intraocular implant + valganciclovir 900 mg PO (b.i.d. for 14-21 days, then once daily) (AI) One dose of intravitreal ganciclovir may be administered immediately after diagnosis until ganciclovir implant can be placed (CIII) For small peripheral lesions Valganciclovir PO daily (BII) Preferred therapy for CMV esophagitis or colitis Ganciclovir IV or foscarnet IV for 21-28 days or until resolution of signs and symptoms (BII) Oral valganciclovir may be used if symptoms are not severe enough to interfere with oral absorption (BII). Maintenance therapy is usually not necessary, but should be considered after relapses (BII). Preferred therapy for CMV pneumonitis Treatment should be considered in patients with histologic evidence of CMV pneumonitis and who do not respond to treatment of other pathogens (AIII)	Alternative therapy for CMV retinitis Ganciclovir 5 mg/kg IV q12h for 14-21 days, then 5 mg/kg IV daily (AI); or Ganciclovir 5 mg/kg IV q12h for 14-21 days, then valganciclovir 900 mg PO daily (AI); or Foscarnet 60 mg/kg IV q8h or 90 mg/kg IV q12h for 14-21 days, then 90-120 mg/kg IV q24h (AI); or Cidofovir 5 mg/kg/week IV for 2 weeks, then 5 mg/kg every other week with saline hydration before and after therapy and probenecid 2 g PO 3 hours before the dose followed by 1 g PO 2 hours after the dose, and 1 g PO 8 hours after the dose (total of 4 g) (AI) Note: This regimen should be avoided in patients with sulfa allergy because of cross hypersensitivity with probenecid
VZV disease	Varicella (chickenpox) Uncomplicated cases Acyclovir (20 mg/kg body weight up to a maximum of 800 mg PO 5 × daily), valacyclovir 1,000 mg PO t.i.d., or famciclovir 500 mg PO t.i.d. × 5-7 days (AII)	Infection caused by acyclovir-resistant VZV Foscarnet 90 mg/kg IV q12h (AII)
	Severe or complicated cases Acyclovir 10-15 mg/kg IV q8h × 7-10 days (AIII) May switch to oral acyclovir, famciclovir, or valacyclovir after defervescence if no evidence of visceral involvement is evident (AIII)
	PORN Ganciclovir 5 mg/kg IV q12h, plus foscarnet 90 mg/kg IV q12h, plus ganciclovir 2 mg/0.05 mL intravitreal twice weekly, and/or foscarnet 1.2 mg/0.05 mL intravitreal twice weekly (AIII) Optimization of ART (AIII)
	ARN Acyclovir 10 mg/kg IV q8h × 10-14 days, followed by valacyclovir 1,000 mg PO t.i.d. × 6 weeks (AIII)
HHV-8 diseases (KS, PEL, MCD)	Initiation or optimization of ART should be done for all patients with KS, PEL, or MCD (BII).
	Preferred therapy for visceral KS *(BII)*, disseminated cutaneous KS *(CIII)*, and PEL *(BIII)* Chemotherapy + ART (BII) Oral valganciclovir or IV ganciclovir might be useful as adjunctive therapy in PEL (BII)
	Preferred therapy for MCD Valganciclovir 900 mg PO b.i.d. (BII); or Ganciclovir 5 mg/kg IV q12h (BII)	Alternative therapy for MCD Rituximab 375 mg/m² given weekly × 4-8 weeks, may be an alternative to antiviral therapy (BII)
HHV-6 infection	If HHV-6 has been identified as cause of disease in HIV-infected patients, use same drugs and doses as treatment for CMV disease (CIII) Ganciclovir (or valganciclovir) Foscarnet
HPV disease	Treatment of condylomata acuminata (genital warts)	Provider-applied therapy
	Patient-applied therapy Podofilox 0.5% solution or 0.5% gel—apply to all lesions b.i.d. × 3 consecutive days, followed by 4 days of no therapy, repeat weekly for up to four cycles (BIII); or Imiquimod 5% cream—apply to lesion at bedtime and remove in the morning on three nonconsecutive nights weekly for up to 16 weeks. Each treatment should be washed with soap and water 6-10 hours after application (BII)	Cryotherapy (liquid nitrogen or cryoprobe)—apply until each lesion is thoroughly frozen; repeat every 1-2 weeks. Some providers allow the lesion to thaw, then freeze a second time in each session (BIII) Trichloroacetic acid or bichloroacetic acid cauterization —80%-90% aqueous solution, apply to each lesion, repeat weekly for 3-6 weeks (BIII) Surgical excision (BIII) or laser surgery (CIII) 100% efficacy.
Ratings Scheme for Prevention and Treatment Recommendations—Category Definition: A, Both strong evidence for efficacy and substantial clinical benefit support recommendation for use. Should always be offered. B, Moderate evidence for efficacy—or strong evidence for efficacy but only limited clinical benefit—supports recommendation for use. Should generally be offered. C, Evidence for efficacy is insufficient to support a recommendation for or against use. Or evidence for efficacy might not out-weight adverse consequences Optional. D, Moderate evidence for lack of efficacy or for adverse out-come supports a recommendation against use. Should generally not be offered. Quality of the Evidence Supporting the Recommendation: I, Evidence from at least one properly designed randomized, controlled trial. II, Evidence from at least one well-designed clinical trial without randomization, from cohort or case-controlled analytic studies (preferably from more than one center), or from multiple time-series studies, or dramatic results from uncontrolled experiments. III, Evidence from opinion of respected. ART, antiretroviral therapy; b.i.d., twice a day; b.i.w., twice weekly, t.i.d., three times a day; t.i.w., three times weekly; g, gram; IM, intramuscular; IV, intravenous; µL, microliter; mg, milligram; PO, oral. Based on Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Morb Mortal Wkly Rep 2009;58:1-198.