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Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents Parasitic Infections Slide Set Prepared by.

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Presentation on theme: "Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents Parasitic Infections Slide Set Prepared by."— Presentation transcript:

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 About This Presentation
These slides were developed using recommendations published in May 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 Users are cautioned that, because of the rapidly changing field of HIV care, this information could become out of date quickly.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 May 2013

3 Parasites Toxoplasma gondii encephalitis Cryptosporidiosis
Microsporidiosis Malaria May 2013

4 Parasites Toxoplasma gondii encephalitis

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 May 2013

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 May 2013

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 May 2013

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 May 2013

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 May 2013

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 May 2013

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 %, sensitivity 50% May 2013

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

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

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 May 2013

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 May 2013

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. May 2013

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 May 2013

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 < cells/µL May 2013

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 mg PO QD For weight >60 kg: pyrimethamine 75 mg PO QD + sulfadiazine 1,500 mg PO Q6H + leucovorin mg PO QD Duration: ≥6 weeks, longer if extensive disease or incomplete response at 6 weeks The initial therapy of choice consists of the combination of pyrimethamine plus sulfadiazine plus leucovorin ( ) (AI). Pyrimethamine penetrates the brain parenchyma efficiently even in the absence of inflammation (126). Use of leucovorin prevents the hematologic toxicities associated with pyrimethamine therapy (127,128). The preferred alternative regimen for patients unable to tolerate or who fail to respond to first-line therapy is pyrimethamine plus clindamycin plus leucovorin (122,123) (AI). Acute therapy should be continued for at least 6 weeks, if there is clinical and radiologic improvement ( ) (BII). Longer courses might be appropriate if clinical or radiologic disease is extensive or if response is incomplete at 6 weeks. May 2013

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 TMP-SMX was reported in a small (77 patient) randomized trial to be effective and better tolerated than pyrimethamine-sulfadiazine (129). On the basis of less in vitro activity and less experience with this regimen, pyrimethamine plus sulfadiazine with leucovorin is the preferred therapy (BI). For patients who cannot take an oral regimen, no well-studied options exist. No parenteral formulation of pyrimethamine exists; the only widely available parenteral sulfonamide is the sulfamethoxazole component of TMP-SMX. Therefore, certain specialists will treat severely ill patients requiring parenteral therapy initially with oral pyrimethamine plus parenteral TMP-SMX or parenteral clindamycin (CIII). Treating Opportunistic Infections Among HIV-Infected Adults and Adolescents – Page 11 At least 3 regimens have activity in the treatment of TE in at least 2 nonrandomized, uncontrolled trials, although their relative efficacy compared with the previous regimens is unknown: 1) atovaquone (with meals or oral nutritional supplements) plus pyrimethamine plus leucovorin (130) (BII); 2) atovaquone combined with sulfadiazine or, for patients intolerant of both pyrimethamine and sulfadiazine, as a single agent (130) (BII) (If atovaquone is used alone, measuring plasma levels might be helpful, given the high variability of absorption of the drug among different patients; plasma levels of >18.5 µg/mL are associated with an improved response rate) (131–133); and 3) azithromycin plus pyrimethamine plus leucovorin daily (134,135) (BII). The following regimens have been reported to have activity in the treatment of TE in small cohorts of patients or in case reports of one or a few patients: clarithromycin plus pyrimethamine (136) (CIII); 5-fluoro-uracil plus clindamycin (137) (CIII), dapsone plus pyrimethamine plus leucovorin (138) (CIII); and minocycline or doxycycline combined with either pyrimethamine plus leucovorin, sulfadiazine, or clarithromycin (139,140) (CIII). Although the clarithromycin dosage used in the only published study was 1 g twice a day, dosages >500 mg have been associated with increased mortality in HIV-1–infected patients treated for disseminated MAC. Dosages >500 mg twice a day should not be used (DIII). May 2013

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 Adjunctive corticosteroids (eg, dexamethasone) should be administered when clinically indicated only for treatment of a mass effect associated with focal lesions or associated edema (BIII). Because of the potential immunosuppressive effects of corticosteroids, they should be discontinued as soon as clinically feasible. Patients receiving corticosteroids should be closely monitored for the development of other OIs, including cytomegalovirus retinitis and TB disease. Anticonvulsants should be administered to patients with a history of seizures (AIII), but should not be administered prophylactically to all patients (DIII). Anticonvulsants, if administered, should be continued at least through the period of acute therapy. May 2013

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 Adjunctive corticosteroids (eg, dexamethasone) should be administered when clinically indicated only for treatment of a mass effect associated with focal lesions or associated edema (BIII). Because of the potential immunosuppressive effects of corticosteroids, they should be discontinued as soon as clinically feasible. Patients receiving corticosteroids should be closely monitored for the development of other OIs, including cytomegalovirus retinitis and TB disease. Anticonvulsants should be administered to patients with a history of seizures (AIII), but should not be administered prophylactically to all patients (DIII). Anticonvulsants, if administered, should be continued at least through the period of acute therapy. May 2013

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 May 2013

24 Toxoplasma gondii Encephalitis: Monitoring and Adverse Events (2)
IRIS appears to occur rarely May 2013

25 Toxoplasma gondii Encephalitis: Treatment Failure
Clinical or radiologic deterioration during first week of therapy, or lack of clinical improvement within 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 May 2013

26 Toxoplasma gondii Encephalitis: Preventing Recurrence
Secondary prophylaxis: Preferred: Pyrimethamine mg PO QD + sulfadiazine 2,000-4,000 mg PO daily in 2-4 divided doses + leucovorin mg PO QD Alternative: Clindamycin 600 mg PO Q8H + pyrimethamine mg PO QD + leucovorin 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 May 2013

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 May 2013

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 May 2013

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 May 2013

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 May 2013

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 May 2013

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 May 2013

33 Parasites Cryptosporidiosis

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 May 2013

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 May 2013

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 May 2013

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 May 2013

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 May 2013

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

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 May 2013

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 May 2013

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 May 2013

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 May 2013

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) May 2013

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 days + ART and other measures above Limited data; may improve clinical response in conjunction with ART May 2013

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 May 2013

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

48 Cryptosporidiosis: Treatment Failure
Supportive treatment Optimization of ART May 2013

49 Cryptosporidiosis: Prevention of Recurrence
No effective prevention, other than immune restoration with ART May 2013

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 May 2013

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 May 2013

52 Parasites Microsporidiosis

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 May 2013

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 May 2013

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 May 2013

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 May 2013

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 May 2013

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 May 2013

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 May 2013

60 Microsporidiosis: Starting ART
ART should be offered as part of initial management of this infection May 2013

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

62 Microsporidiosis: Treatment Failure
Supportive treatment Optimization of ART May 2013

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) May 2013

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 May 2013

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 May 2013

66 Websites to Access the Guidelines
May 2013

67 About This Slide Set 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: May 2013


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