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HIV II

HIV II. Update on Opportunistic Infections Prevention and Treatment. Pathophysiology. Depletion of CD-4 cells (T-helper) HIV binds Cell entry cell death. Direct mechanisms Accumulation of unintegrated viral DNA Interference with cellular RNA processing

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HIV II

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  1. HIV II Update on Opportunistic Infections Prevention and Treatment

  2. Pathophysiology • Depletion of CD-4 cells (T-helper) • HIV binds • Cell entry • cell death

  3. Direct mechanisms Accumulation of unintegrated viral DNA Interference with cellular RNA processing Intracellular gp 120-CD4 autofusion events Loss of plasma membrane integrity because of viral budding Elimination of HIV-infected cells by virus-specific immune responses Indirect mechanisms Aberrant intracellular signaling events Syncytium formation Autoimmunity Superantigenic stimulation Innocent bystander killing of viral antigen-coated cells Apoptosis Inhibition of lymphopoiesis CD4-deficiency

  4. CD4 depletion syndromes • HIV/AIDS • idiopathic CD4+ T lymphocytopenia • Iatrogenic • Corticosteroids • Immunosuppressants

  5. Opportunistic infections For patients taking potent combination antiretroviral therapy (ART), beginning in 1996, there has been a dramatic decline in the incidence of AIDS-related opportunisticinfections (OIs) such as Pneumocystis carinii pneumonia (PCP), disseminated Mycobacterium avium complex (MAC), and invasive cytomegalovirus (CMV) disease

  6. Treatment Guidelines • Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents: http://www.cdc.gov/mmwr/pdf/rr/rr5804.pdf

  7. Major Changes in Guidelines • Increased emphasis on importance of ART • More information about IRIS • Information about using IGRAs for latent TB diagnosis • More drug interactions data • Addition of section on Hepatitis B treatment • Addition of section on malaria.

  8. ART therapy in OI • Benefits of ART have been demonstrated for cryptosporidiosis, PML, microsporidiosis, KS and other relatively untreatable OIs • Recommend begin ART (AIII) • KS essentially goes away • However, institution of ART during an OI can result in an exuberant immune response • Drug/drug interaction can also be difficult

  9. ART therapy in OI • TB, MAC, PCP, crytococcal infection • Highest association with IRIS • Wait for clinical response to OI rx before starting ART (CIII) • When OI develops within first 12 weeks of ART initiation, begin OI rx and do not stop ART (AIII) • A RCT demonstrated a clinical and survival benefit of starting ART withint the first 2 wks of initiation of rx for OI, except for TB Zolopa A, Andersen J, Komarow L, et al. Immediate versus deferred ART in the setting of acute AIDS-related OI: final results of a randomized strategy trial, ACTG A5164. 15th CROI;2008; Boston, MA. Abstract 142.

  10. Management of acute OI after starting ART • First group: within 12 wks, may be unmasked, therefore don’t represent failure of ART • >/= 12 wks with high CD4 (IRIS vs failure of ART?) • >/= 12wks after ART with virologic failure

  11. HIV and fever • Disseminated MAC • before HAART, most common cause of FUO in advanced AIDS. • Disseminated histo • bartonellosis • CMV • cryptococcosis

  12. Disseminated FUO Fever, night sweats, weight loss, diarrhea Anemia, elevated alkaline phosphatase GI Visceral pulmonary Localized "immune reconstitution" illnesses biopsies show a granulomatous response lymphadenitis (mesenteric, cervical, thoracic) can mimic Pott's disease with disease presenting in the spine or other bones/joints Pulmonary Mycobacterium avium-intracellulare complex (MAC)

  13. Findings Adenopathy Elevated alk phos anemia Diagnosis Blood culture Tissue culture Histopathology Treatment Macrolide + ethambutol + rifabutin Amikacin ciprofloxacin MAC

  14. MAC • Sources • Food • Water • soil • Stool screening not rec b/c no data for benefit, although predicts disease • No recs for avoidance

  15. MAC prophylaxis • Primary CD4 < 50 until >100 3 mo. (AI) • Clarithromycin • Azithromycin • Rifabutin (not combo-EI) • Exclude TB • DI’s • Secondary for 12 mo and until no sx and CD4 >100 6 mo (BCx neg) • Macrolide + ethambutol, +/- rifabutin • High dose clarithromycin asso. W/higher mortality (EI) • Clofazimine too many ADR’s (DII) • Restart at CD4 <50-100

  16. Azithromycin not affected by c P450 Protease inhibitors Increase clarithromycin levels Some contraindicated w/rifabutin NNRTIs (efavirenz) Induce clarithromycin metabolism Some contraindicated w/rifabutin Drug Interactions

  17. Manifestations Bacillary angiomatosis (BQ) Lymphadenitis (BH) Hepatosplenic disease (BH) peliosis hepatis GI Brain neuropsych bone B. henselae and B. quintana Treatment Erythromycin Tetracycline deriv. Bartonella

  18. Bartonellosis • HIV-higher incidence • Older cats less likely to transmit • Control fleas • No rec for primary prophylaxis • Consider long-term suppression (C-III)

  19. Risk groups MSM IDU Childcare exposure Test IgG if lower risk group Not IDU/MSM % IgG positive Varies by country CMV

  20. Manifestations FUO pancytopenia CNS Retinitis Blurred vision scotomata field cuts Encephalitis Transverse myelitis Radiculitis pneumonitis GI Gastritis/GU DU colitis CMV

  21. Diagnosis Serology-not helpful Tissue histopathology Molecular diagnostics Antigen PCR Treatment Valganciclovir Ganciclovir 5 mg/kg IV bid × 14-21 days Foscarnet 60 mg/kg IV q8h or 90 mg/kg IV q12h × 14-21 days Cidofovir 5 mg/kg IV weekly × 2 then every other week Implants CMV

  22. Primary Can consider if IgG (+) and CD4 <50 Oral ganciclovir or valganciclovir Regular optho exams Discuss symptoms NOT acyclovir/valacyclovir Secondary Intraocular alone not sufficient Valganciclovir Consider stopping when CD4>100-150 6mo Continue regular f/u CMV-neg or leukopoor irradiated blood if CMV (-) CMVprophylaxis

  23. Cryptosporidium Microsporidiosis Isospora Giardia bacterial enteric infections Salmonella Shigella campylobacter Listeria CMV Cdiff HIV and diarrhea

  24. HIV and diarrhea • Crampy abdominal pain, bloating, and nausea suggest small bowel • Cryptosporidia • Microsporidia • Isospora • Giardia • cyclospora) • MAC. • High-volume, watery diarrhea with weight loss and electrolyte disturbance is most characteristic of cryptosporidiosis • bloody stools with abdominal cramping and fever ( invasive bacterial pathogen) • Clostridium difficile • CMV colitis

  25. Stool studies O&P Trichrome AFB Immunohisto Cdiff Thorough history Medication review Low threshold for flex sig Given the availability of effective treatment; more aggressive evaluation that often includes endoscopy has replaced the less invasive approach. Treatment Antimotility agents Imodium, Lomotil Opium Calcium octreotide HIV and diarrhea

  26. Seek vet care for animals with diarrhea WASH HANDS Travel precautions Bottled beverages Avoid fresh produce Avoid ice Consider prophylaxis or early empiric therapy Cipro 500 qd Bactrim Avoid Reptiles, chicks and ducklings Raw eggs Raw poultry, meat and seafood Unpasteurized dairy products/juices Raw seed sprouts Soft cheeses Deli counters unless can reheat Refrigerated meat spreads Bacterial Enteric InfectionsPrevention

  27. coccidian protozoan (I. belli, C. cayetanensis, and Toxoplasma gondii) 5%-10% of diarrhea in immunocompetent Asymptomatic carriers mammalian hosts-cattle, horses, rabbits, guinea pigs, mice. transmission fecal-oral. Waterborne outbreaks due to contamination of drinking water thick-walled, highly resistant oocyst excysts in stomach sporozoites infect enterocytes and persist at the apical pole of intestinal epithelial cells-microscopic appearance of extracellular, adherent parasite Cryptosporidium

  28. biopsy fecal examination Modifed AFB Immunohisto stains Treatment Azithromycin Paromomycin (Octreotide-now DII) nitazoxanide HAART Clarithromycin/rifabutin work, but no data. Counsel regarding exposure-avoid feces Private room Diapers Animals with diarrhea young animals (screen BIII) water boil water when suggested (AI) filters (CIII) oysters bottled (CIII) Cryptosporidiosisprevention

  29. observed initially in intestinal biopsy specimens in 1982 No disease in normal hosts 2 types Enterocytozoon bieneusi, reproduces within enterocytes Encephalitozoon (Septata) intestinalis infects epithelial cells and stromal cells of the lamina propria and causes systemic infection Diagnosis Difficult to see by light microscopy-order trichrome stain Treatment Albendazole (for intestinalis) Atovaquone metronidazole. nitazoxanide No recs for prevention Microsporidiosis

  30. Isospora • no other known host • endemic in Brazil, Colombia, Chile, and parts of equatorial Africa and southwest Asia. • seen rarely in normals • fecal-oral route

  31. Immunocompetent watery diarrhea usually clear the infection within about 2 weeks; may persist HIV-chronic high-volume watery diarrhea Detection in stool samples difficult, and concentration or flotation methods. AFB + histologic sections Villus atrophy, eosinophil infiltrates, and disorganization of the epithelium shown better with Giemsa on histo Cipro better than Bactrim Isospora

  32. Cyclospora • first reported in the 1980s • endemic in tropical countries and other areas w/poor standards of hygiene and water purification • severity related to the degree of immunosuppression • Rx Bactrim

  33. Cyclospora • Epidemics attributed to contamination of water supplies, fruits, and vegetables • similar to Cryptosporidium but larger (8 to 10 mum versus 4 to 5 mum) and AFB + • fecal-oral route • intermittent watery diarrhea for 3 > mo. • infect enterocytes and proliferate within a supranuclear parasitophorous vacuole.

  34. PCP histoplasmosis cryptococcosis rhodococcus CMV Pneumococcus 100-fold risk Nontypable H. flu Pseudomonas 40-fold risk Lowest CD4 HHV-8 Coccidiodomycosis HIV and pneumonia

  35. PCP

  36. PCP • Symptoms • Incidious onset • SOB>cough • pneumothorax • Findings • diffuse infiltrates in a perihilar or bibasilar distribution and a reticular or reticulonodular pattern • No effusion • Elevated LDH • SX>>>CXR • Normal in 26% • Extrapulmonary disease

  37. PCP • Microbiology • P. jiroveci infects human • P. carinii infects rodents • Fungus with protozoal properties • Primary infection usually early childhood • Diagnosis (preferred) • Expectorated sputum much less sensitive • Sputum for DFA • Sputum cytology • BAL for same • Histopathology/stains • Mortality 60% in patients requiring mechanical vent

  38. PCP • TMP 15 mg/kg/d + SMX 75 mg/kg/d po or IV × 21 days in 3-4 divided doses; for outpatient, 2 DS tablets po tid (AI) rash, fever, gastrointestinal symptoms, hepatitis, hyperkalemia, leukopenia, and hemolytic anemia • Steroid (pO2 < 70 or A-a gradient > 35)-21d taper (AI) • Alternatives • TMP-dapsone (BI) • Clinda/primaquine (BI) • Atovaquone (less effective in mild-mod) (BI) • Trimetrexate/folinic acid (keep fol for 3 d after last dose)-(AI) • Iv Pentam (BI) nausea, infusion-related hypotension, hypoglycemia, hypocalcemia, renal failure, and pancreatitis

  39. CD4<200 or history of oral thrush (AII) CD4%<14 or other OI (BII) Bactrim (AI) DS daily (toxo, bacterial pathogens) SS daily DS TIW (BII) rechallenge if rash (desens) - 70% tolerate PCPprophylaxis

  40. Dapsone Dapsone + pyrimethamine/leucovorin aerosolized pentam (Respirgard II)-pregnancy 1st term atovaquone Other aerosolized Pentam parenteral pentam oral pyrimethamine/ sulfadoxine oral clinda/primaquine trimetrexate PCPprophylaxis All BI All CIII

  41. Stop when CD4>200 for 3 mo. Restart if CD4<200 Stop secondary prophylaxis if CD4>200 unless PCP occurred at higher CD4 Children of HIV mothers need prophylaxis Children with PCP can not stop secondary prophylaxis. PCPprophylaxis

  42. Mississippi valley and Ohio valley + worldwide Normal hosts usually asympto or mild URI-no rx THE MOST common endemic mycosis Pulmonary, mucosal, disseminated or CNS Respiratory culture Blood culture Bone marrow biopsy Urine Ag Some cross reaction More sensitive in dissem disease, esp HIV Rx ampho, itra Histoplasmosis

  43. Clin Chest Med - 01-DEC-1996; 17(4): 725-44

  44. Routine skin testing not predictive Avoid Creating soil/old building dust Cleaning chicken coops Disturbing bird roosts Exploring caves Secondary prophylaxis Itraconazole No data-no rec for stopping Primary Prophylaxis No proven survival benefit Consider in high risk and CD4<100 HistoplasmosisPrevention

  45. Increased mortality with Pneumococcal Increased incidence of Pseudomonas Bactrim and macrolide prophylaxis prevent resp infections, but not rec solely for this reason Maintain normal granulocyte count & IgG Prevention PCV-13 followed by polysaccharide vaccine Typical CAP

  46. Low threshold of suspicion Lower CD4=atypical presentation Higher mortality Tuberculin skin testing (TST) negative in 40% of patients with disease 4-drug therapy initially Drug interactions major issue Tuberculosis

  47. Tuberculosis prevention • PPD for all new diagnoses • Consider annual if continued risk • Employment • Homeless • Foreign travel

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