• Candida infections: the most common fungal infections in HIV patients.
• Often occur early in HIV disease.
• May signify onset of clinical manifestation of immunodeficiency.
• Generally easy to control
• Range of infections:
  • Oral cavity (thrush): white, exudate on posterior oropharynx.
  • In late stages of HIV infection (see for T cell accounts less than 100 per microliter):
    • Candida infections: esophagus, lungs, bronchi, trachea -- -- indicative of severe immunodeficiency.
    • Esophagitis, not responsive to therapy directed at Candida,may be due to an other causes, such as, cytomegalovirus infection, HSV, Kaposi sarcoma, lymphoma

Treatment

• Oral or vaginal Candida: topical nystatin (Mycostatin) or clotrimazole (Mycelex) troches.
• In severe cases: systemic therapy-- ketoconazole (Nizoral) or fluconazole (Diflucan)
  • Fluconazole (Diflucan) may be preferable (ketoconazole (Nizoral)e may be less well absorbed in patients with high gastric pH)
• Another option for management of severe cases: IV amphotericin B (Fungizone, Amphotec), then oral fluconazole (Diflucan).

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• Leading cause of meningitis in HIV patients.
• Cryptococcus neoformans, a fungus: -- life threatening infection in 6% to 12% of AIDS patients.
• Generally occurs with advanced disease (CD4 T cell counts < 100 per microliter)
•  Cryptococcus neoformans enters the body through the respiratory tract, but the infection sites are generally the brain and meninges.[CNS infection -- 67% to 85%]
  •  Patients present with subacute meningioencephalitis
  •  Patients, in addition to meningitis, may present with cryptococcoma.
  •  Common symptoms:
    •  fever (frequency: 100%)
    •  altered mental status
    •  headache
    •  meningeal signs
  •  Pulmonary manifestation: 40% of patients with CNS infection
    •  Common symptoms:
      •  fever
      •  cough
      •  dyspnea
  • Definitive diagnosis: organism culture from spinal fluid, blood, bone marrow, sputum, or tissue

Cryptococcal Infections: Treatment

• Therapy: initiated immediately when antigen or culture tests our positive for cryptococcal infection
• Standard therapy in HIV patients:amphotericin B (Fungizone, Amphotec) in combination with flucytosine (Ancobon)..
  • Due to neutropenia, more than half of patients will not be able to receive the full course of flucytosine (Ancobon) treatment.
• Since over 50 percent of HIV patients will suffer a relapse, following amphotericin B (Fungizone, Amphotec) treatment, patients should be maintained on fluconazole (Diflucan) indefinitely.
• Fluconazole (Diflucan) is sometimes used as prophylaxis against candidal and cryptococcal infections when CD₄ T cell count < 100 per microliter.

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• Most commonly seen:in regions where Histoplasma capsulatum is endemic. (Mississippi and Ohio River Valley).
• For these geographic reasons, there are about 0. 5% of histoplasmosis-AIDS cases in the United States overall.
• Generally a late manifestation of HIV (median CD₄T cell count for patients with histoplasmosis -- 33 per microliter); occasionally, histoplasmosis is the first presenting clinical indication.
• Histoplasma capsulatum:may present initially as a pulmonary infection,disseminated disease is the most common clinical presentation in HIV.
• Clinical presentations:
  • fever
  • weight loss
  • lymphadenopathy
  • hepatosplenomegaly
  • Bone marrow involvement (33%):
    •  thrombocytopenia
    •  neutropenia
    • anemia
  • Abnormal chest x-ray (50% of patients: diffuse interstitial infiltrate or diffuse small nodules)
• Diagnosis: organism culture from blood, bone marrow, or tissue.
• Treatment: initially --amphotericin B (Fungizone, Amphotec): maintenance -- amphotericin B (Fungizone, Amphotec) or oral itraconazole (Sporanox).

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•  Significant problem throughout the course of HIV infection.
• Viral infections of special concern:
  • Cytomegalovirus (CMV)
  • Herpes simplex virus
  • Varicella zoster virus
  • Epstein-Barr virus

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•  In HIV, the clinical problem is the re-activation of latent CMV.
• Clinical presentations:
  • generally late in HIV disease (CD₄ T cell count < 50 per microliter)
  • Retinitis
    •  perhaps the most devastating manifestation (frequency:25% to 30%)
    •  progressive, painless loss of vision
    • usually bilateral; diagnosis: direct clinical assessment by an experienced ophthalmologist
    • retinal appearance:perivascular hemorrhage and exudate.
    • Necrotic inflammatory process: reversible vision loss
  • Esophagitis
    • Presentations: chest pain (substernal); odynophagia (pain on swallowing)
    • Diagnosis: endoscopy -- usually reveals distal esophageal bolster
  • Colitis
    • Frequency:5% to 10% of AIDS patients.
    • Clinical presentations:
      • diarrhea
      • abdominal pain
      • weight loss
      • anorexia
    • Diagnosis: endoscopy -- usually reveals multiple mucosal ulcerations.
      • Barium enema may be appear normal; consequently, HIV patients with CMV colitis may suffer abdominal perforation and bacteremia.
  • some other CMV manifestations in HIV patients:
    • pneumonia
    • ascending myelitis
    • subacute polyneuropathy

Cytomegalovirus Treatment

• Three major drugs for treatment of systemic CMV infection: Ganciclovir (DHPG, Cytovene), Cidofovir, Foscarnet
• Ganciclovir (DHPG, Cytovene) and cidofovir (Vistide): available as ocular implants.

• Retinitis: (photograph )
  • Initial response rates: 80% to 90% following ganciclovir or foscarnet. [Ganciclovir-easier to administer for initial therapy]
    •  Ganciclovir (DHPG, Cytovene): high incidence of bone marrow suppression -- may not be given in combination with zidovudine or trimethoprim/sulfamethoxazole.
    •   Foscarnet (Foscavir): high incidence of renal/electrolyte disorders
    •  Maintenance therapy is required following initial response -- note relapse rates are very high.
      • Oral ganciclovir is licensed for CMV prophylaxis -- oral ganciclovir delays the development of CMV disease
    • In patients without renal dysfunction, patients treated with foscarnet (Foscavir)exhibited slightly longer survival then those treated with ganciclovir (DHPG, Cytovene)r. (Perhaps because foscarnet has activity against HIV as well as CMV)
    • One common protocol involves initial treatment with ganciclovir and maintenance treatment with foscarnet
    •  Ganciclovir (DHPG, Cytovene)-resistant strains would be treated with either cidofovir or foscarnet
    •  Cidofovir (Vistide)-- less potent, however easier to administer
      • cidofovir (Vistide) side effects: leukopenia, weakness, nausea, diarrhea, decreased intraocular pressure

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• Associated with orolabial, genital, perianal lesions.
• Frequency and severity of infections increase as CD₄ T cell count decreases.
• HSV may also cause esophagitis, manifested at multiple small ulcers.
• HSV and VZV rarely cause a widespread, bilateral necrotizing retinitis: acute retinal necrosis syndrome.--characterized by kerititis, pain, iritis.

HSV Treatment

• Severe or recurrent HSV: acyclovir (Zovirax)
• Alternative: famciclovir (Famvir)
•  Valacyclovir (Valtrex), Although effective for recurrent herpes simplex in HIV, valacyclovir should be avoided because of reported fatal cases of thrombotic thrombocytopenic purpura
• Herpes strains resistant to acyclovir are increasingly common; these resistant strains are also resistant to ganciclovir -- sensitivity to foscarnet usually remains.

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• Varicella zoster virus: (chickenpox); latent in dorsal root ganglia after initial infection.
• Shingles occur or upon reactivation.
• Shingles in a patient under 50 years of age may suggest immunodeficiency, including HIV.
• Shingles is an early indication of HIV-induced immunodeficiency.
• Clinical presentation:
  • VZV infection in HIV is usually confined to the skin
  • Acute retinal necrosis syndrome: rarely seen, associated with trigeminal shingles.
•  Primary infection (not recurrent) may be fatal -- should be aggressively treated with acyclovir (Zovirax) and hyperimmuune globulin.
• If shingles are treated, lesions may resolve more quickly
  • treatment options: high-dose oral or IV acyclovir (Zovirax) or oral famciclovir (Famvir); acyclovir (Zovirax)-resistant strains-- foscarnet (Foscavir)

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• Epstein-Barr virus: a cause of infectious mononucleosis-- a common infection in HIV patients.
• May play a role in causing oral hairy leukoplakia (white lesions-- lateral aspect of the tongue and adjacent buccal mucosa --sometimes confused with candidiasis, but lesions cannot be removed by scraping).
• May be associated with lymphoma.

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• Human herpesvirus 8 (HHV-8): associated with Kaposi's sarcoma lesions and body cavity lymphoma in HIV patients -- no specific treatment
• Human herpesvirus 6:causes exanthem subitum in infants(remittant fever lasting three days, followed by crisis then a few hours later by a rash on the trunk)
• JC virus infection: human papovarvirus --causes progressive multifocal leukoencephalopathy (PML); important opportunistic pathogen in AIDS patients.
  • Demyelinating disease, beginning as subcortical white matter foci; eventually cerebral hemispheres, cerebellum, and brain stem involvement.
  • Protracted clinical course: multifocal neurological deficits:
    • ataxia, hemiparesis, visual field defects, aphasia, sensory defects.
  • Possible Treatment: intrathecal cytosine arabinoside; no consistently effective treatment presently available (1997)
• Human Papilloma virus: common in HIV patients (about two times more common than in general population)
  • Virus is associated with epidural dysplasia.
• Hepatitis viruses:
  • Nearly all of HIV-infected individuals show evidence of hepatitis B infection.
  • Co-infection with hepatitis C and/or D is common;
  • presence of HIV infection may slightly worsen hepatic disease;
  • Patients with HIV infection may respond more poorly to IFN-alpha therapy for hepatitis B then non-HIV patients.

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