1. Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents Parasitic Infections Slide Set Prepared by the AETC National Resource Center based on recommendations from the CDC, National Institutes of Health, and HIV Medicine Association/Infectious Diseases Society of America

2. May 2013www.aidsetc.org 2 About This Presentation These slides were developed using recommendations published in May 2013. The intended audience is clinicians involved in the care of patients with HIV. Users are cautioned that, because of the rapidly changing field of HIV care, this information could become out of date quickly. Finally, it is intended that these slides be used as prepared, without changes in either content or attribution. Users are asked to honor this intent. -AETC National Resource Center http://www.aidsetc.org

3. May 2013www.aidsetc.org 3 Parasites  Toxoplasma gondii encephalitis  Cryptosporidiosis  Microsporidiosis  Malaria

4. Parasites Toxoplasma gondii encephalitis

5. May 2013www.aidsetc.org 5 Toxoplasma gondii Encephalitis: Epidemiology  Caused by the T gondii protozoan  Disease almost always caused by reactivation of latent tissue cysts  Primary infection may be associated with acute cerebral or disseminated disease  Seroprevalence varies widely: 11% in the United States, 50-80% in some European, Latin American, and African countries

6. May 2013www.aidsetc.org 6 Toxoplasma gondii Encephalitis: Epidemiology (2)  In advanced AIDS, 12-month incidence of TE was 33% among Toxoplasma-seropositive patients who were not on prophylaxis or ART  Among seronegative persons, toxoplasmosis is rare  Occurs primarily in patients with CD4 counts of <200 cells/µL, especially <50 cells/µL  Incidence and mortality lower in United States and Europe owing to widespread use of prophylaxis and potent ART

7. May 2013www.aidsetc.org 7 Toxoplasma gondii Encephalitis: Epidemiology (3)  Primary infection acquired from tissue cysts in undercooked meat or raw shellfish, or ingestion of sporulated oocysts (from cat feces) in soil, water, or food  No transmission by person-to-person contact

8. May 2013www.aidsetc.org 8 Toxoplasma gondii Encephalitis: Clinical Manifestations  Focal encephalitis with headache, confusion, or motor weakness and fever  May have nonfocal symptoms, including nonspecific headache and psychiatric symptoms  May have focal neurological abnormalities; may progress to seizures, altered mental status, coma  Retinochoroiditis, pneumonia, other organ involvement are rare

9. May 2013www.aidsetc.org 9 Toxoplasma gondii Encephalitis: Clinical Manifestations  CT or MRI:  Typical findings are multiple contrast-enhancing lesions in gray matter of cortex or basal ganglia, often associated edema  May show single brain lesion, or diffuse encephalitis without focal lesions

10. May 2013www.aidsetc.org 10 Toxoplasma gondii Encephalitis: Diagnosis  Serum anti-Toxoplasma IgG  Positive in almost all patients with TE; negative IgG makes diagnosis unlikely but not impossible  IgM usually negative  Definitive diagnosis: compatible clinical syndrome + mass lesion(s) on imaging + detection of organism in a clinical sample (brain biopsy)  CT, MRI of brain: typically multiple contrast-enhancing lesions, often with edema  MRI better than CT for radiological diagnosis  PET or SPECT may help distinguish TE from lymphoma

11. May 2013www.aidsetc.org 11 Toxoplasma gondii Encephalitis: Diagnosis (2)  Check CSF (if safe and feasible) for T gondii PCR, cytology, culture, cryptococcal antigen, PCR for M tuberculosis, EBV, JC virus  CSF PCR specificity for T gondii is 96-100%, sensitivity 50%

12. May 2013www.aidsetc.org 12 Toxoplasma gondii Encephalitis: Diagnosis (3)  Differential diagnosis of focal neurological disease  CNS lymphoma, PML, mycobacterial infection (TB), fungal infection, Chagas disease, abscess

13. May 2013www.aidsetc.org 13 Toxoplasma gondii Encephalitis: Diagnosis (4) Credit: P. Volberding, MD; UCSF Center for HIV Information Image Library CT scan of the brain showing contrast- enhancing lesion of toxoplasmosis

14. May 2013www.aidsetc.org 14 Toxoplasma gondii Encephalitis: Diagnosis (5)  May initially make empiric diagnosis, established on basis of clinical and radiographic improvement to TE therapy, in absence of a likely alternative diagnosis  Brain biopsy if failure to respond to therapy, or if initial studies suggest etiology other than TE

15. May 2013www.aidsetc.org 15 Toxoplasma gondii Encephalitis: Preventing Exposure  All HIV+ should be tested for IgG to Toxoplasma at baseline, to detect latent infection  Toxoplasma seronegative: counsel about sources of infection  Patients: avoid eating raw or undercooked meat or shellfish; wash hands after handling raw meat and after contact with soil; wash fruits/vegetables; clean cat-litter boxes daily and wash hands afterward; cats should not be fed raw/undercooked meats

16. May 2013www.aidsetc.org 16 Toxoplasma gondii Encephalitis: Primary Prophylaxis For all Toxoplasma IgG positive with CD4 count <100 cells/µL  Recommended:  TMP-SMX 1 DS QD  Alternative:  TMP-SMX 1 DS PO TIW  TMP-SMX 1 SS QD  Dapsone* 50 mg PO QD + pyrimethamine 50 mg PO Q week + leucovorin 25 mg PO Q week  Dapsone* 200 mg PO Q week + pyrimethamine 75 mg PO Q week + leucovorin 25 mg PO Q week  Atovaquone 1,500 mg PO QD +/- pyrimethamine 25 mg PO QD + leucovorin 10 mg PO QD * Avoid dapsone if patient has G6PD deficiency; screen before treatment with dapsone, if possible.

17. May 2013www.aidsetc.org 17 Toxoplasma gondii Encephalitis: Primary Prophylaxis (2)  Toxoplasma seronegative patients: retest for Toxoplasma IgG if CD4 count declines to <100 cells/µL, unless taking PCP prophylaxis that also is active against TE

18. May 2013www.aidsetc.org 18 Toxoplasma gondii Encephalitis: Discontinuing Primary Prophylaxis  Discontinue if on effective ART with CD4 count of >200 cells/µL for >3 months  Restart prophylaxis if CD4 count decreases to <100-200 cells/µL

19. May 2013www.aidsetc.org 19 Toxoplasma gondii Encephalitis: Treatment  Preferred:  Pyrimethamine 200 mg PO 1 dose, then:  For weight ≤60 kg: pyrimethamine 50 mg PO QD + sulfadiazine 1,000 mg PO Q6H + leucovorin 10- 25 mg PO QD  For weight >60 kg: pyrimethamine 75 mg PO QD + sulfadiazine 1,500 mg PO Q6H + leucovorin 10- 25 mg PO QD  Duration: ≥6 weeks, longer if extensive disease or incomplete response at 6 weeks

20. May 2013www.aidsetc.org 20 Toxoplasma gondii Encephalitis: Treatment (2)  Alternative:  Pyrimethamine as above + clindamycin 600 mg IV or PO Q6H + leucovorin as above  TMP-SMX (5 mg/kg TMP and 25 mg/kg SMX) IV or PO BID  Atovaquone 1,500 mg PO BID + pyrimethamine, as above + leucovorin as above  Atovaquone 1,500 mg PO BID + sulfadiazine (weight- based as above)  Atovaquone 1,500 mg PO BID (variable absorption)  Pyrimethamine as above + azithromycin 900-1,200 mg PO QD + leucovorin as above

21. May 2013www.aidsetc.org 21 Toxoplasma gondii Encephalitis: Treatment (3)  Adjunctive corticosteroids only if indicated for treatment of mass effect; monitor closely and discontinue as soon as possible  Anticonvulsants if history of seizures; continue at least through period of acute therapy  Should not be given prophylactically to all patients

22. May 2013www.aidsetc.org 22 Toxoplasma gondii Encephalitis: ART Initiation  No data to guide recommendation on when to start ART  Many recommend starting ART within 2-3 weeks after diagnosis of TE  In one study, lower rate of AIDS progression or death with early ART

23. May 2013www.aidsetc.org 23 Toxoplasma gondii Encephalitis: Monitoring and Adverse Events  Follow clinical and radiologic improvement  Ab titers not useful  Monitor for adverse events  Pyrimethamine: rash, nausea, bone marrow suppression  May be reversed with increase in leucovorin dosage  Sulfadiazine: rash, fever, leukopenia, hepatitis, nausea, vomiting, diarrhea, renal insufficiency, crystalluria  Clindamycin: rash, fever, nausea, diarrhea (including Clostridium difficile colitis), hepatotoxicity  TMP-SMX: rash, fever, leukopenia, thrombocytopenia, hepatotoxicity  Atovaquone: nausea, vomiting, diarrhea, rash, headache, hyperglycemia, fever

24. May 2013www.aidsetc.org 24 Toxoplasma gondii Encephalitis: Monitoring and Adverse Events (2)  IRIS appears to occur rarely

25. May 2013www.aidsetc.org 25 Toxoplasma gondii Encephalitis: Treatment Failure  Clinical or radiologic deterioration during first week of therapy, or lack of clinical improvement within 10-14 days  Brain biopsy, if not done previously  If confirmed TE, consider switch to alternative treatment regimen  In patients who adhere to treatment, recurrence is unusual during maintenance therapy following initial clinical and radiographic response

26. May 2013www.aidsetc.org 26 Toxoplasma gondii Encephalitis: Preventing Recurrence  Secondary prophylaxis:  Preferred:  Pyrimethamine 25-50 mg PO QD + sulfadiazine 2,000-4,000 mg PO daily in 2-4 divided doses + leucovorin 10-25 mg PO QD  Alternative:  Clindamycin 600 mg PO Q8H + pyrimethamine 25-50 mg PO QD + leucovorin 10-25 mg PO QD (not effective as PCP prophylaxis)  TMP-SMX DS 1 tablet BID  Atovaquone 750-1,500 mg PO BID + pyrimethamine 25 mg PO QD (+ leucovorin 10 mg PO QD)  Atovaquone 750-1,500 mg PO BID + sulfadiazine 2,000-4,000 mg PO daily in 2-4 divided doses  Atovaquone 750-1,500 mg PO BID

27. May 2013www.aidsetc.org 27 Toxoplasma gondii Encephalitis: Preventing Recurrence (2)  Discontinuing maintenance therapy: consider in asymptomatic patients after successful initial therapy for TE, resolution of signs and symptoms of TE, and sustained increase in CD4 count to >200 cells/µL for >6 months, on ART  Consider brain MRI before treatment discontinuation; continue therapy if mass lesions present or enhancement persists  Restart secondary prophylaxis if CD4 count decreases to <200 cells/µL

28. May 2013www.aidsetc.org 28 Toxoplasma gondii Encephalitis: Considerations in Pregnancy  Check T gondii IgG during pregnancy  If suspected or confirmed T gondii infection, evaluate and manage with a maternal-fetal specialist  Diagnostic considerations same as for nonpregnant women

29. May 2013www.aidsetc.org 29 Toxoplasma gondii Encephalitis: Considerations in Pregnancy (2)  Perinatal transmission usually occurs only with acute maternal infection; case reports of transmission with reactivation of chronic infection in women with severe immunosuppression  If toxoplasmosis during pregnancy (primary infection or reactivation of chronic toxoplasmosis):  Detailed ultrasound of fetus  Consider PCR of amniotic fluid in select circumstances  Neonate should be evaluated for evidence of congenital infection

30. May 2013www.aidsetc.org 30 Toxoplasma gondii Encephalitis: Considerations in Pregnancy (3)  Primary prophylaxis: recommended  TMP-SMX preferred  Balance possible risks with expected benefits  Treatment: as in nonpregnant adults  Secondary prophylaxis: as in nonpregnant women

31. May 2013www.aidsetc.org 31 Toxoplasma gondii Encephalitis: Considerations in Pregnancy (4)  Pyrimethamine appears safe in human pregnancy  Sulfadiazine appears safe though, if given around time of delivery, may increase risk of neonatal kernicterus  Clindamycin considered same in pregnancy  Dapsone: risk of mild maternal hemolysis with long-term therapy; low risk of hemolytic anemia in exposed fetuses with G6PD deficiency

32. May 2013www.aidsetc.org 32 Toxoplasma gondii Encephalitis: Considerations in Pregnancy (5)  Consider immediate initiation of ART, to decrease risk of perinatal HIV transmission, especially for women diagnosed with TE in 3rd trimester  Preconception care for women receiving TE prophylaxis: discuss option of deferring pregnancy until TE prophylaxis can be discontinued safely

33. Parasites Cryptosporidiosis

34. May 2013www.aidsetc.org 34 Cryptosporidiosis: Epidemiology  Caused by Cryptosporidium species  Protozoan parasites  Infect small intestine mucosa; in immunosuppressed patients, also infect large intestine and other sites  Advanced immunosuppression (eg, CD4 <100 cells/µL) associated with prolonged, severe, or extraintestinal disease

35. May 2013www.aidsetc.org 35 Cryptosporidiosis: Epidemiology (2)  Infection results from ingestion of oocysts excreted in feces of infected humans or animals  Water supplies and recreational water sources (oocysts may withstand standard chlorination)  Person-to-person transmission common, via oral-anal contact, from infected children to adults (eg, during diapering), or care of patients with diarrhea

36. May 2013www.aidsetc.org 36 Cryptosporidiosis: Epidemiology (3)  Common cause of chronic diarrhea in AIDS patients in developing countries  In developed countries with low rates of envrionmental contamination and widespread use of effective ART, <1 case per 1,000 person-years in AIDS patients

37. May 2013www.aidsetc.org 37 Cryptosporidiosis: Clinical Manifestations  Acute or subacute onset of profuse watery, nonbloody diarrhea, often with nausea, vomiting, and abdominal cramping  Fever in 1/3 of patients  Can be very severe, especially with immune suppression  Malabsorption is common; dehydration, electrolyte abnormalities, malnutrition may result  Biliary tract and pancreatic duct may be infected, causing scleroding cholangitis and pancreatitis  Pulmonary infection is possible

38. May 2013www.aidsetc.org 38 Cryptosporidiosis: Diagnosis  Microscopic identification of oocysts in stool or tissue  DFA very sensitive, specific, is current gold standard for stool specimens  Acid-fast staining often used  PCR extremely sensitive  ELISA or immunochromatographic tests  Small intestine biopsy with identification of Cryptosporidium organisms

39. May 2013www.aidsetc.org 39 Cryptosporidiosis: Diagnosis (2)  Single specimen usually sufficient in profuse diarrhea  Repeat stool sampling is recommended in mild disease

40. May 2013www.aidsetc.org 40 Cryptosporidiosis: Prevention Preventing exposure  Avoid exposure to infected contacts  Contact with diarrhea  Potential oral exposure to feces during sex  Direct contact with farm animals, stool from pets  Scrupulous handwashing after potential contact with feces (eg, after diapering), after handling pets or other animals, gardening, before preparing food or eating, before and after sex

41. May 2013www.aidsetc.org 41 Cryptosporidiosis: Prevention (2)  Avoid exposure to contaminated water, food  Do not drink or swallow water from recreational sources (lakes, streams, pools)  Ice, fountain beverages, water fountains may be contaminated  Avoid raw oysters

42. May 2013www.aidsetc.org 42 Cryptosporidiosis: Prevention (3)  Boil tap water for ≥1 minute during outbreaks or when community advisory is issued  Submicron water filters or bottled water may reduce risk  For non-outbreak settings, data are inadequate to recommend that all persons with low CD4 counts avoid drinking tap water  Consider drinking only filtered water

43. May 2013www.aidsetc.org 43 Cryptosporidiosis: Prevention (4) Preventing disease  Primary prophylaxis:  Appropriate initiation of ART before severe immunosuppression should prevent disease  Rifabutin and possibly clarithromycin are protective, but data insufficient to recommend as chemoprophylaxis

44. May 2013www.aidsetc.org 44 Cryptosporidiosis: Treatment  Preferred strategies  ART with immune restoration (to CD4 count >100 cells/µL)  Usually results in complete resolution; should be offered as part of initial management of cryptosporidiosis  Symptomatic treatment: antidiarrheals  Tincture of opium may be more effective than loperamide  Octreotide usually not recommended (no more effective than other antidiarrheals)  Supportive care: aggressive hydration, electrolyte repletion, nutritional support (IV therapies may be needed)

45. May 2013www.aidsetc.org 45 Cryptosporidiosis: Treatment (2)  Alternative strategies  No consistently effective antimicrobial therapy in absence of ART  Consider nitazoxanide or other antiparasitic drugs in conjunction with ART, not instead of ART  Nitazoxanide 500-1,000 mg PO BID for 14 days + ART and other measures above  Some studies show clinical improvement with nitazoxanide  Paromomycin 500 mg PO QID for 14-21 days + ART and other measures above  Limited data; may improve clinical response in conjunction with ART

46. May 2013www.aidsetc.org 46 Cryptosporidiosis: Starting ART  ART should be offered as part of initial management of this infection  PIs inhibit Cryptosporidium in animal models – some experts prefer PI-based ART

47. May 2013www.aidsetc.org 47 Cryptosporidiosis: Monitoring and Adverse Events  Monitor closely for volume depletion, electrolyte loss, weight loss, and malnutrition  TPN may be indicated  IRIS not reported

48. May 2013www.aidsetc.org 48 Cryptosporidiosis: Treatment Failure  Supportive treatment  Optimization of ART

49. May 2013www.aidsetc.org 49 Cryptosporidiosis: Prevention of Recurrence  No effective prevention, other than immune restoration with ART

50. May 2013www.aidsetc.org 50 Cryptosporidiosis: Considerations in Pregnancy  Rehydration and ART initiation as with nonpregnant adults  Nitazoxanide not teratogenic in animals, but no data in pregnant humans  Use after 1st trimester in severely symptomatic women  Paromomycin: limited information on teratogenicity; minimal systemic absorption with PO administration  Use after 1st trimester in severely symptomatic women

51. May 2013www.aidsetc.org 51 Cryptosporidiosis: Considerations in Pregnancy (2)  Loperamide: possible risk of hypospadias with 1st-trimester exposure  Avoid during 1st trimester, unless benefits expected to outweigh risks  Preferred antimotility agent during late pregnancy  Tincture of opium not recommended during late pregnancy  Opiate exposure during late pregnancy associated with neonatal respiratory depression; chronic exposure may result in neonatal withdrawal

52. Parasites Microsporidiosis

53. May 2013www.aidsetc.org 53 Microsporidiosis: Epidemiology  Protists, related to fungi  Many species, including Enterocytozoon bieneusi, Encephalitozoon cuniculi, Encephalitozoon intestinalis  Ubiquitous, may be zoonotic and/or waterborne  Risk greatest with CD4 count <100 cells/µL  Incidence dramatically lower in areas with widespread use of effective ART

54. May 2013www.aidsetc.org 54 Microsporidiosis: Clinical Manifestations  Most common: diarrheal illness  Other manifestations: cholangitis, hepatitis, encephalitis, ocular infection, sinusitis, myositis, disseminated infection  Clinical syndromes may vary by species

55. May 2013www.aidsetc.org 55 Microsporidiosis: Diagnosis  Microscopic identification of stool or tissue samples  Identification requires high magnification (1,000×), selective stains to differentiate spores from cellular debris  Electron microscopy, PCR, Ab-specific stains can determine species  Evaluate 3 stool samples  Small bowel biopsy if stool studies are negative and suspicion is high  Urine examination may be useful if cause is Encephalitozoon or Trachipleistophora spp

56. May 2013www.aidsetc.org 56 Microsporidiosis: Prevention  Preventing exposure  Handwashing; avoidance of undercooked meat or seafood and exposure to infected animals  Patients with CD4 counts of <200 cells/μL should avoid drinking untreated water  Primary prophylaxis  Appropriate initiation of ART before severe immunosuppression should prevent disease  No chemoprophylaxis known to be effective

57. May 2013www.aidsetc.org 57 Microsporidiosis: Treatment  ART with immune restoration (to CD4 count >100 cells/µL)  Should be offered to all as part of initial management  If severe dehydration, malnutrition, wasting: hydration, nutritional support (IV therapies may be needed)  Antimotility agents, if needed for diarrhea control

58. May 2013www.aidsetc.org 58 Microsporidiosis: Treatment (2)  E bieneusi GI infections:  ART and fluid support as above  no specific antimicrobial;  Fumagillin 60 mg PO QD or TNP-470: some evidence of efficacy but not available in United States  Nitazoxanide: limited data; cannot be recommended with confidence  Nonocular infection caused by microsporidial other than E bieneusi and V corneae:  Albendazole 400 mg PO BID

59. May 2013www.aidsetc.org 59 Microsporidiosis: Treatment (3)  Disseminated disease caused by Trachipleistophora or Anncaliia  Itraconazole 400 mg PO QD + albendazole 400 mg PO BID  Ocular infection: fumagillin (Fumidil B) eye drops 70 mcg/mL + albendazole 400 mg PO BID

60. May 2013www.aidsetc.org 60 Microsporidiosis: Starting ART  ART should be offered as part of initial management of this infection

61. May 2013www.aidsetc.org 61 Microsporidiosis: Adverse Events  Albendazole: adverse effects are rare; monitor hepatic enzymes  Fumagillin  Topical: no known substantial side effects  Oral: thrombocytopenia  IRIS: 1 report

62. May 2013www.aidsetc.org 62 Microsporidiosis: Treatment Failure  Supportive treatment  Optimization of ART

63. May 2013www.aidsetc.org 63 Microsporidiosis: Prevention of Recurrence  Ocular:  If CD4 >200 cells/µL on ART, consider discontinuing treatment after ocular infection resolves; restart if CD4 drops to <200 cells/µL  Other manifestations:  Safety of treatment discontinuation after immune restoration with ART is not known  Reasonable to discontinue maintenance therapy in asymptomatic patients on ART with increase in CD4 count to >200 cells/µL for ≥6 months (no data to support this approach)

64. May 2013www.aidsetc.org 64 Microsporidiosis: Considerations in Pregnancy  Initiate ART to restore immune function  Albendazole:  Embryotoxic and teratogenic in animals  Not recommended in 1st trimester, use during later pregnancy only if benefits expected to outweigh risks  Systemic fumagillin: growth retardation in rats: should not be used with pregnant women  Topical fumagillin appears safe

65. May 2013www.aidsetc.org 65 Microsporidiosis: Considerations in Pregnancy (2)  Itraconazole: avoid in 1st trimester  Loperamide: possible risk of hypospadias with 1st-trimester exposure  Avoid in 1st trimester, unless benefits expected to outweigh risks  Preferred antimotility agent during late pregnancy  Tincture of opium not recommended during late pregnancy  Opiate exposure during late pregnancy associated with neonatal respiratory depression; chronic exposure may result in neonatal withdrawal

66. May 2013www.aidsetc.org 66 Websites to Access the Guidelines  http://www.aidsetc.org  http://aidsinfo.nih.gov

67. May 2013www.aidsetc.org 67  This presentation was prepared by Susa Coffey, MD, and Oliver Bacon, MD, for the AETC National Resource Center in May 2013  See the AETC NRC website for the most current version of this presentation: http://www.aidsetc.org About This Slide Set