Opportunistic Infections and other associated conditions in HIV

Opportunistic Infection Prophylaxis

Prophylaxis for OIs: primary and secondary prophylaxis

• • Primary prophylaxis before an episode of OI occurs.

    • Not routinely recommended for: recurrent bacterial pneumonia, mucosal candidiasis, CMV retinitis, cryptococcosis, and endemic fungal infections such as histoplasmosis and coccidiodomycosis.

  • Secondary prophylaxis is instituted after an episode of infection is adequately established.

  • Withdrawal of prophylaxis. Recommendations suggest when sustained immunologic recovery has occurred (CD4 cell counts consistently above 150 - 200 cells/mm3)

Immune reconstitution syndrome (IRIS), generally presents as local inflammatory reactions. Examples include paradoxical reactions with TB reactivation, localized MAC adenitis, and CMV vitreitis immediately after initiation of potent ART. Hepatitis virus infections can be aggravated with the immune reconstitution associated with ART. Tx with continuation of ART and addition of low-dose steroids to decrease the degree of inflammation.

VIRAL INFECTIONS

• • CMV retinitis seen in patients with CD4 cell count <50 cells/mm3.

    • Treatment: includes two phases, induction and maintenance.

    • Valganciclovir, a ganciclovir prodrug is approved for use in CMV retinitis. Drug levels are equivalent to those of IV ganciclovir.

      • Valganciclovir, 900 mg PO bid x 21 days, followed by 900 mg PO qd. Treatment is indefinite unless immunologic recovery occurs. Adverse effects are similar to those of ganciclovir.

    • Ganciclovir is given at an induction of 5 mg/kg IV bid for 14 - 21 days, and maintenance dose of 5 mg/kg IV daily indefinitely (unless immune reconstitution occurs).

      • Side effect: ganciclovir is myelotoxic resulting in neutropenia. GCSF therapy is sometimes needed.

    • Alternatives include Foscarnet IV, Cidofovir IV, and Fomivirsen IO (intraocular, does not provide systemic therapy). Foscarnet and Cidofovir IV administration carry a significant risk of nephrotoxicity, therefore, adequate hydration and electrolyte monitoring are required.

    • For other invasive CMV disease, the optimal therapy is with ganciclovir IV, valganciclovir PO, foscarnet IV, or a combination of two drugs for at least 3 - 6 weeks. Foscarnet has the best CSF penetration and is the drug of choice for CMV encephalitis and myelopathy.

  • VZV may cause typical dermatomal lesions or disseminated infection. May cause encephalitis, which is more common with ophthalmic distribution of facial nerve.

    • Tx: Acyclovir, 10 mg/kg IV q8h for 7 - 14 days. For milder cases, acyclovir, 800 mg PO, 5 times a day, or famciclovir 500 mg PO tid, or valacyclovir, 1 g PO tid x 1 week

  • JC virus is associated with progressive multifocal leukoencephalopathy (PML). Sx include mental status changes, weakness, and disorders of gait. Characteristic periventricular and subcortical white matter lesions are seen on MRI.

    • Tx: Potent ART has improved the survival of patients with PML.

  • Parvovirus B19 infection can cause pure red cell (RBC) aplasia. Relapses are frequent. Tx: IV immunoglobulin, 0.4 g/kg IV daily for 10 days.

  • Chronic Hepatitis C has a significant impact on morbidity and mortality in HIV inf patients. Sustained virologic response rates are lower specifically in the genotype I. Tx: Combination of pegylated interferon-alpha and ribavirin.

  • Chronic Hepatitis B has a significant impact on morbidity and mortality in HIV inf patients. Determine the need for HIV treatment. Antiretroviral combination of TDF/FTC (or 3TC) as part of HAART. If HIV does not require treatment, then use pegylated interferon-alpha, adefovir or telbivudine.

MYCOBACTERIAL INFECTIONS

• • Mycobacterium TB is more frequent in HIV patients, particularly IV drug abusers. Primary or reactivated disease is common.

    • Diagnosis:

      • Clinical manifestations depend on level of immunosuppression.

      • Pts with higher CD4 cell counts tend to exhibit classic presentation with apical cavitary disease.

      • Immunosuppressed pts can have atypical presentations that can resemble disseminated primary inf, diffuse or localized pulmonary infiltrates and hilar LAD.

      • Extrapulmonary dissemination is common.

    • Treatment:

      • Rifabutin, 150 mg daily for 4 months, in patient receiving ritonavir, indinavir, nelfinavir, or fosamprenavir, whereas it should be increased to 450 mg PO daily when combined with nevirapine or efavirenz.

      • INH + pyridoxine for 9 months

      • In ART-naive, ART can be delayed for a few weeks after TB-specific therapy is started.

  • M. Avium Complex (MAC) infection is the most common mycobacterial infection in AIDS patients and is responsible for significant morbidity in patients with CD4 counts <100 cells/mm3.

    • Diagnosis:

      • Disseminated infection with fever, wt. loss, and night sweats is the most frequent presentation.

      • MAC infection can result in bacteremia in AIDS patients.

      • Anemia, ▲ alkaline phosphatase level, mycobacterial blood cultures should be sent in suspected cases.

    • Treatment:

      • Macrolide (azithromycin 1200 mg PO weekly OR clarithromycin, 500 mg PO bid) and ehtambutol, 15 mg/kg PO daily.

      • Rifabutin, 300 mg PO daily, or ciprofloxacin, 500 mg PO bid, can be added in severe cases.

      • D/c secondary prophylaxis for disseminated MAC if the CD count had a sustained increase >100 cells/mm3 for 6 months or longer in response to ART, and if 12 months of therapy for MAC is completed and there are no symptoms or signs attributable to MAC.

FUNGAL INFECTIONS

• • Pneumocystis jiroveci Pneumonia (PjP) is the most common infection in patients with AIDS and is the leading cause of death in this population.

    • Treatment:

      • TMP/SMX is drug of choice. TMP 5 mg/kg IV q6 - 8 h for severe cases, with a switch to PO when the patient's condition improves. Total duration of Tx is 21 days. Prednisone should be added if PaO2 <70 mm Hg or an P(A-a)O2 gradient >35 mm Hg. Prednisone 40 mg PO bid on days 1 - 5 and 20 mg PO bid on days 6 - 10, followed by 10 mg PO daily on days 11 - 21.

      • Patients who cannot receive TMP/SMX:

        • Mild to moderately severe disease, PaO2 >70 mm Hg or P(A-a)O2 <35 mm Hg

          • TMP, 20 mg/kg/d PO, and dapsone, 100 mg PO daily. G6PD deficiency should be ruled out before dapsone is used.

          • Clindamycin, 600 mg IV or PO tid + primaquine, 15 mg PO daily. G6PD should be ruled out before primaquine is used.

          • Atovaquone, 750 mg PO tid. The drug should be given with meals to increase absorption.

        • For severe disease (PaO2 <70 mm Hg or P(A-a)O2 >35 mm Hg):

          • Prednisone taper should be added. 40 mg PO bid on days 1-5 and 20 mg PO bid on days 6-10, followed by 10 mg PO on days 11-21.

          • IV Pentamidine or Trimetixate are used on all cases when other options are exhausted. Both drug required close monitoring for side effects.

        • Secondary prophylaxis can be d/c if the CD4 count is >200 cells/mm3 for more than 3 months as a result of ART treatment.

  • Candidiasis is a common infection in HIV-infected host.

    • Diagnosis: oral, esophageal, or vaginal.

    • Treatment:

      • Oral and vaginal candidiasis respond to local therapy with troches or creams (nystatin or clotrimazole).

      • Pts who do not respond or who have esophageal candidiasis, fluconazole 100 - 200 mg PO daily is the treatment of choice.

      • Fluconazole resistant candidiasis is increasing especially in patients with advanced disease who have been receiving antifungal agents for prolonged periods.

      • Caspofungin, an echinocandin, is effective in refractory cases using an induction dose of 70 mg IV on day 1 and then 50 mg IV daily for maintenance.

      • Itraconazole oral suspension, 200 mg bid is occasionally effective. Many patients require amphotericin B, either as an oral suspension 100 mg/mL swish and swallow qid or parenterally.

      • Voriconazole may also be useful.

  • Cryptococcus Neoformans. Meningitis is the most frequent CNS fungal infection in AIDS patients.

    • Dx: HA, fever, and possibly mental status changes, but presentation can be more subtle.

      • Can present as pulmonary or cutaneous disease.

      • Diagnosis is based on LP results and on the determination of latex cryptococcal anigen, which is usually positive in the serum and in the CSF. CSF opening pressure should always be measured to assess the possibility of elevated ICP.

    • Treatment:

      • Initial treatment is with amphotericin B, 0.7 mg/kg/d IV, and 5-flucytosine, 25 mg/kg PO q6h for 2 - 3 weeks, followed by fluconazole, 400 PO daily for 8 - 10 weeks and then 200 mg PO indefinitely.

      • 5-flucytosine level should be monitored during therapy to avoid toxicity. A lipid preparation of amphotericin can be used in patients with renal insufficiency.

      • Repeat LP (removing up to 30 mL CSF until the pressure is below 20 - 25 cm H2O) may be needed to relieve elevated ICP.

      • In persons who have persistent elevation of ICP, a temporary lumbar drain is indicated.

  • Histoplasma capsulatum infection occurs in AIDS patients who live in endemic areas such as the Mississippi and Ohio River Valleys. Infections are usually disseminated at the time of diagnosis.

    • Dx:

      • Suspect histoplasmosis in patients with fever, hepatosplenomegaly, and weight loss. Pancytopenia develops due to bone marrow involvement.

      • Diagnosis is made by a positive culture, but the urine Histoplasma antigen can also be used for the diagnosis and to monitor treatment.

    • Tx:

      • Amphotericin B, 0.5 mg/kg IV daily for a total dose of 0.5 - 1 gm, followed by itraconazole, 300 mg PO bid for 3 days for induction therapy, followed by 200 mg PO bid indefinitely.

      • Itraconazole absorption should be documented by a serum drug level.

      • D/c of itraconazole is possible if sustained release in CD4 count is observed >100 to 200 cells/mm3 for more than 6 months.

  • Coccidioides immitis is frequent in AIDs patients in endemic areas of the southwestern US. Extensive disease with extra-pulmonary spread. Diagnosis is made by a positive culture, serum detection of IgM and IgG by immunodiffusion, and complement fixation.

    • Tx: Amphotericin B therapy initially, followed by lifelong suppression with fluconazole, 400 mg PO daily, or itraconazole, 200 mg PO bid. Coccidioidal meningitis requires intracisternal or intraventricular therapy with amphotericin B. Fluconazole may also be effective.

PROTOZOAL INFECTIONS

• • Toxoplasma gondii typically causes CNS lesions - encephalopathy and focal neurologic findings.

    • Dxtic: serology.

      • MRI of the brain is the best radiographic technique for diagnosis.

      • Often the diagnosis relies on response to empiric treatment, as seen by reduction of the size of the mass lesions.

    • Tx:

      • Sulfadiazine, 25 mg/kg PO q6h, + pyrimethamine, 100 mg PO on day 1, followed by 75 mg PO daily, is the therapy of choice.

        • For patients who are allergic to sulfonamides, clindamycin 600 mg IV or PO q8h can be used instead of sulfadiazine.

      • Leucovorin, 5 - 10 mg PO daily, should be added to prevent hematologic toxicity.

      • Doses are reduced after 3 - 6 weeks of therapy.

      • Indications for prophylaxis: when CD4 <100 cells/mm3. TMP/SMX DS PO daily.

      • Secondary prophylaxis can be d/c among patients with a sustained increase in CD4 count >200 cells/mm3 for more than 6 months as a result of response to ART and if the initial therapy is complete and there are no sx or signs attributable to Pneumocystis.

  • Cryptosporidium causes watery diarrhea with malabsorption in HIV-infected patients.

    • Dxtic: visualization of the parasite in an acid-fast stain of stool.

    • Tx: No effective specific therapy.

      • Nitazoxanide, 500 mg PO bid, may be effective.

      • Potent ART also has been reported to be effective.

  • Cyclospora causes chronic diarrhea

    • Tx: TMP/SMX - DS, 1 tab PO bid x 7 - 10 days, is usually effective.

  • Isospora Belli causes chronic diarrhea

    • Tx: TMP/SMX - DS, 1 tab PO qid x 10 days, followed by chronic suppression with TMP/SMX - DS, 1 tab PO daily is effective.

  • Microsporidia can produce diarrhea and biliary tree disease in patients with advanced infection.

    • Dxtic: Difficult and needs special staining of the stool. Enterocytozoon bieneusi and Encephalitozoon intestinalis are the microsporidia most commonly found. E. intestinalis can cause disseminated disease.

    • Tx: Albendazole, 400 mg PO bid. Relapses are common when treatment is stopped.

  • Strongyloides presents with disseminated infection in AIDS patients from endemic areas (Southeastern US, immigrants from tropical and subtropical countries).

    • Tx: Thiabendazole, 22 mg/kg (maximum, 1.5 g) PO daily for 7 - 14 days, is the drug of choice for disseminated strongyloidiasis.

NEOPLASMS

• • Kaposi Sarcoma caused by coinfection with human herpes virus 8 (HHV8), a.k.a KSHV. It is usually a cutaneous lesion, but can occur in GI tract and lungs.

    • Tx: Local therapy with liquid nitrogen or intralesional injection with alitretinoin or vinblastine has been used. Cryotherapy or radiation therapy may be useful as well. Systemic therapy involves chemotherapy (e.g., liposomal doxorubicin, paclitaxel, liposomal daunorubicin, thalidomide, retinoids), radiation, and interferon-alpha.

  • Lymphomas associated with AIDS are NHL, CNS and systemic lymphomas, and lymphomas of B-cell origin.

    • EBV appears to be the associated pathogen.

    • Dx: Primary CNS lymphomas are common and can be multicentric.

      • Diagnosis is based on clinical sx, presence of enhancing brain lesions, brain bx, and a positive EBV-PCR of the CSF. Other OI need to be ruled out. Other potential extranodal sites of involvement including bone marrow, GI tract, and liver require tissue bx to confirm the diagnosis.

    • Tx: chemotherapy and radiation.

  • Cervical and Perinanal Neoplasias: Both HIV men and women are at high risk for HPV-related disease.

    • HPV subtypes 16 and 18 are oncogenic. Cancer can also arise from perianal condyloma acuminata.

    • Dx: Screening for vaginal dysplasia with a PAP smear q6mo x 1 year, and if the results are normal, annually afterwards. Screening for anal intraepithelial neoplasms.

STI

• • Genital Herpes: HSV-2 and less frequently HSV-1 caused genital and perirectal lesions.

    • Dx: HSV serology, HSV-PCR from the genital fluid, viral culture.

    • Tx: Acyclovir, 400 mg PO tid, famiciclovir, 250 mg PO tid, or valacyclovir, 500 mg PO tid x 1 week is usually effective. For more severe disease, acyclovir, 5 mg/kg IV q8h. Replapses are frequent, and prophylactic acyclovir, 400 mg PO bid may prevent recurrence as part of suppressive or episodic treatment strategy. If resistant HSV, foscarnet, 40 mg/kg IV q8h for 10 - 14 days, or one dose of cidofovir, 5 mg/kg IV, should be used.

  • Genital warts are caused by HPV. HPV types 6 and 11 are common. Others are (16, 18, 31, and 33) commonly associated with malignant transformation. Genital wart in HIV infected persons are typically more resistant to treatment in addition to a higher chance of recurrence (http://www.cdc.gov/STD/treatment/2006/genital-warts.htm)

    • Dx: clinical, and bx of lesion.

    • Tx: local therapy

  • Syphilis can have an atypical course in HIV-infected patients. Tx failures have been reported.

    • Dx: LP should be performed in HIV-infected patients with latent syphilis to rule out neurosyphilis

    • Tx: Benzathine penicillin, 2 - 4 million units IM x 1 for primary syphilis. For secondary syphilis, Benzathine penicillin, 2 - 4 million units IM weekly for 3 weeks. Also same regimen for latent syphilis (of >1 year duration). Doxycycline, 100 mg PO bid x 14 days, is an alternative. If neurosyphilis is present, penicillin G, 12 - 24 million units IV daily for 14 days, is the only approved treatment of choice. Patients who are allergic to penicillin should be desensitized. Data regarding use of ceftriaxone, 1 - 2 g IV daily x 14 days is limited.

    • Close monitoring using the nontreponemal test at 3, 6, 12 months are necessary in all cases.

    • Patients with a sustained positive nontreponemal titer should receive retreatment and be considered for CSF evaluation to rule out neurosyphilis.

BACTERIAL INFECTIONS

• • Bacillary angiomatosis caused by Bartonella henselae.

    • Characterized by multiple nodular, purplish lesions on the skin and other organs.

    • Tx: Erythromycin 500 mg PO q6h. Alternatives: Doxycycline, 100 mg PO bid; other macrolides and ciprofloxacin, 500 mg PO bid.

  • Campylobacter jejuni causes GI or disseminated infections.

    • Tx: Erythromycin, 500 mg PO qid, or ciprofloxacin, 500 mg PO bid, can be used.

  • Rhodococcus equi can cause necrotizing cavitary pneumonia.

    • Tx: Vancomycin, 1 g IV q12h, followed by chronic suppression with erythromycin, 500 mg PO qid, plus rifampin, 600 mg PO daily, or with ciprofloxacin, 500 mg PO bid.

  • Salmonella species can result in recurrent bacteremia in AIDS. It occurs more commonly in men who have sex with men.

    • Antibacterial therapy should be treated on susceptibility pattern.

    • Tx: Ceftriaxone, 1 g IV daily, or ampicillin, 1 g IV q6h, or TMP/SMX, 1 DS tablet PO bid; or ciprofloxacin, 500 mg PO bid.

  • Bacterial pneumonias risk is high in HIV infected patients.

    • S. pneumoniae or H. influenzae. Gram negative rods (especially Pseudomonas aeruginosa).

    • Tx: 3rd generation cephalosporin, or fluoroquinolones or antipseudomonal agent if indicated.

  • M. kansasii frequently occurs in HIV, should always be considered when identified in clinical samples.

    • Clinically the infection appears similar to TB.

    • Tx: Rifampin, 600 mg PO daily, ethambutol, 15 mg/kg/d, PO, and INH, 300 mg PO daily. It requires treatment with a macrolide, rifampin, and two other drugs active against the organism.

  • M. hemophilum infection causes ulcerative skin lesions. It requires treatment with a macrolide, rifampin, and two other drugs active against the organism.