HIV II

1. HIV II Update on Opportunistic Infections Prevention and Treatment

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

4. 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

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

6. 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

7. Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America Prepared by Jonathan E. Kaplan, MD1 Constance Benson, MD2 King K. Holmes, MD, PhD3 John T. Brooks, MD1 Alice Pau, PharmD4 Henry Masur, MD4 1CDC, Atlanta, Georgia 2 University of California San Diego, San Diego, California 3University of Washington, Seattle, Washington 4National Institutes of Health, Bethesda, Maryland

8. However… • Remains a leading cause of morbidity and death in HIV patients because… 1) many patients are unaware of their HIV infection and seek medical care when an OI becomes the initial indicator of their disease; 2) certain patients are aware of their HIV infection, but do not take ART because of psychosocial or economic factors; and 3) certain patients are prescribed ART, but fail to attain adequate virologic and immunologic response because of factors related to adherence, pharmacokinetics, or unexplained biologic factors

9. Furthermore… • The relation between OIs and HIV infection is bidirectional. • HIV leads to immunosuppression that allows opportunistic pathogens to cause disease in HIV-infected persons. • OIs and other coinfections that might be common in HIV-infected persons, such as sexually transmitted infections, can also have adverse effects on the natural history of HIV infection i.e increase viral load and therefore disease progression and transmission. • chemoprophylaxis and vaccination directly prevent pathogen-specific morbidity and mortality, but they might also contribute to reduced rate of progression of HIV disease.

10. Major changes in guidelines • additional emphasis on the importance of ART for prevention and treatment of OIs, especially those for which specific chemoprophylaxis and treatment do not exist • information on diagnosis and management of immune reconstitution inflammatory syndromes (IRIS) • information on interferon-gamma release assays (IGRAs) for the detection of latent Mycobacterium tuberculosis infection • updated information on drug interactions affecting use of rifamycin drugs for prevention and treatment of tuberculosis (TB); 5) addition of a section on hepatitis B virus (HBV) infection; and 6) addition of a section on malaria to the OIs of geographic interest.

11. A Both strong evidence for efficacy and substantial clinical benefit support recommendation for use. Should always be offered. B Moderate evidence for efficacy -- or strong evidence for efficacy but only limited clinical benefit -- supports recommendation for use. Should generally be offered. C Evidence for efficacy is insufficient to support a recommendation for or against use. Or evidence for efficacy might not outweigh adverse consequences (e.g., drug toxicity, drug interactions) or cost of the chemoprophylaxis or alternative approaches. Optional. D Moderate evidence for lack of efficacy or for adverse outcome supports a recommendation against use. Should generally not be offered. E Good evidence for lack of efficacy or for adverse outcome supports a recommendation against use. Should never be offered. RatingStrength of the Recommendation Gross PA, Barrett TL, Dellinger EP, et al. Purpose of quality standards for infectious diseases. Clin Infect Dis 1994; 18(3):421.

12. Quality of evidence supporting the recommendation I Evidence from at least one properly randomized, controlled trial. II Evidence from at least one well-designed clinical trial without randomization, from cohort or case-controlled analytic studies (preferably from more than one center), or from multiple time-series studies. Or dramatic results from uncontrolled experiments. III Evidence from opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees.

13. ART therapy in OI • Benefits of ART have been demonstrated for cryptosporidiosis, PML, microsporidiosis, KS and other relatively untreatable OIs • Recommend begin ART (AIII) • one recently completed randomized clinical trial has demonstrated a clinical and survival benefit of starting ART early, within the first 2 weeks, of initiation of treatment for an acute OI, excluding TB • However, institution of ART during an OI can result in an exuberant immune response (IRIS) • drug/drug interaction can also be difficult

14. ART in acute OI Main point: In cases of cryptosporidiosis, microsporidiosis, PML, KS, PCP, and invasive bacterial infections, the early benefits of ART outweigh increased risk related to these other factors and ART should be started as soon as possible

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

16. 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 Pulmonary Mycobacterium avium-intracellulare complex (MAC)

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

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

19. 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 CD4 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

20. 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

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

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

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

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

25. 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

26. 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

27. Cryptosporidium (nls) Microsporidiosis Isospora Giardia (nls) Cyclospora (nls) bacterial enteric infections Salmonella Shigella campylobacter Listeria CMV Cdiff HIV and diarrhea

28. 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

29. 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

30. 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

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

32. biopsy fecal examination Modifed AFB Immunohisto stains Treatment Azithromycin Paromomycin Octreotide 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

33. 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. No recs for prevention Microsporidiosis

34. 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

35. 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

36. 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

37. 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.

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

41. PCP

42. Symptoms Insidious onset SOB>cough Pneumothorax Before HAART, 70-90% of AIDS pts got PCP, and mort was 20-40% Findings diffuse infiltrates in a perihilar or bibasilar distribution and a reticular or reticulonodular pattern No effusion Elevated LDH SX>>>CXR Normal in 26% Poor air movement Microbiology P. jiroveci infects human P. carinii infects rodents 2/3 of kids are infected by 2-4 yo Fungus with protozoal properties Diagnosis (preferred) Expectorated sputum much less sensitive Sputum for DFA Sputum cytology BAL for same Histopathology/stains Isolation controversial-some rec private room. PCP

43. PCP treatment • 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) • Mortality remains 50% in those requiring ICU or mech ventilation • TMP-dapsone • Clinda/primaquine • Atovaquone • Trimetrexate/folinic acid • Iv Pentam • toxicity

44. PCP treatment complications • methemoglobinemia and hemolysis with dapsone or primaquine (especially in those with G6PD deficiency) • rash and fever with dapsone • azotemia, pancreatitis, hypo- or hyperglycemia, leukopenia, electrolyte abnormalities, and cardiac dysrhythmia with pentamidine • anemia, rash, fever, and diarrhea with primaquine and clindamycin • headache, nausea, diarrhea, rash, and transaminase elevations with atovaquone • IRIS • Treatment failure

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

46. 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

47. Stop when CD4>200 for 3 mo. (AI) 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

48. Pulmonary Complications of HIV Infection Study incidence 3.9–7.3 episodes per 100 person-years preHAART Increased mortality Most common Pneumococcal and H. flu Increased incidence of Pseudomonas and Staph Any age or CD4 Treatment Similar to non HIV but no macrolide alone Be cautious about quinolone if TB suspected IRIS has not been described Typical CAP

49. Typical CAP • Diagnosis • c/w PCP, localized findings on exam • Lower threshold for testing b/c broad diff • BCx higher yield • Prevention • Maintain normal granulocyte count & IgG • Bactrim and macrolide prophylaxis prevent resp infections, but not rec solely for this reason • Stop smoking, excess alcohol or drug use • Flu vaccine (not live) • Pneumovax • BII rec if CD4>200 • No data for CD4<200 (less data) • Repeat in 5 years (even less data) • Repeat when CD4 >200

50. Low threshold of suspicion Lower CD4=atypical presentation Higher mortality Per WHO cause of death in 12% of AIDS cases Tuberculin skin testing (TST) negative in 40% of patients with disease 1/3 of cases are primary in HIV 4-drug therapy initially Drug interactions major issue Associated w/IRIS Tuberculosis