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Opportunistic Infections in the Era of HAART: Are they gone?

South Dakota ACP Annual Meeting September 13, 2012. Opportunistic Infections in the Era of HAART: Are they gone?. Jennifer L. Hsu, MD Sanford Clinic Infectious Disease Assistant Professor, Sanford School of Medicine of The University of South Dakota. Financial Disclosures: None

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Opportunistic Infections in the Era of HAART: Are they gone?

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  1. South Dakota ACP Annual Meeting September 13, 2012 Opportunistic Infections in the Era of HAART: Are they gone? Jennifer L. Hsu, MD Sanford Clinic Infectious Disease Assistant Professor, Sanford School of Medicine of The University of South Dakota Financial Disclosures: None Unlabeled/Unapproved Uses Disclosure: None

  2. Learning Objective • Identify and outline appropriate diagnostic and therapeutic strategies for the most commonly seen HIV-associated infections in the era of highly active antiretroviral therapy.

  3. Incidence of Hospitalization, HIV Outpatient Study, 1994 – 2005 BuchaczK, et al. AIDS 2008;22:1345-56.

  4. Rates of Hospitalization, HIV Outpatient Study, 1994 – 2005 31% 7% 14% 9% BuchaczK, et al. AIDS 2008;22:1345-56.

  5. Incidence of AIDS-Defining OIs, HIV Outpatient Study, 1994 – 2007 High-Frequency Opportunistic Infections BuchaczK, et al. AIDS 2010;24:1549-59.

  6. Rates of OIs: HOPS and NHDS, 1996-2007 Kamimoto, et al. National HIV Prevention Conference 2011, Atlanta, GA, Poster 085M.

  7. OIs and Mortality CASCADE Collaboration. AIDS 2006;20:741-749.

  8. Where do OIs occur in the U.S. now? • Unaware of HIV positivity • Presentation toemergency care with late-stage manifestations of AIDS • Aware of HIV positivity • Remain unlinked to care • Psychosocial or economic factors  unable to take HAART • Poor adherence  poor virologic suppression or immune reconstitution • Extensive antiretroviral resistance • Lack of appropriate infection prophylaxis Brooks J, et al. Clin Infect Dis 2009;48:609-11.

  9. Case 1 • 53 yo male diagnosed with HIV through routine screening – CD4 8 cells/μland HIV RNA 88,000 copies/ml • Presents with persistent fever, fatigue, and weight loss, as well as intermittent diarrhea • BP 116/56|Pulse 84|Temp 38.1 °C|SpO2 97% • Exam notable for cachexia, diffuse abdtendernesswith hepatosplenomegaly

  10. Case 1 (cont.) • Abnormal labs: • Hct 24% • Alkaline phosphatase 360 • CT: hepatosplenomegaly with multiple enlarged nodes

  11. Which of the following the most appropriate next step? • Initiate ART and prophylaxis with TMP-sulfa and azithromycin. • Lymph node biopsy. • Bone marrow biopsy. • Blood culture for acid-fast organisms. • Initiate 4-drug therapy for tuberculosis.

  12. MAC Basics • Most common bacterial OI in developed world • Affects 10-20% of persons living with AIDS • Independent predictor of mortality even when adjusted for CD4 count Incidence of MAC infection in patients with a CD4 count <200/L, Johns Hopkins HIV clinic cohort, 1991–2003 Moore RDand Chaisson RE. Ann Intern Med 1996;124:633–42. KarasouksisP, et al. Lancet Infect Dis 2004;4:557-65.

  13. Survival with MAC, Johns Hopkins HIV Clinic Cohort, Pre- vs. Post-HAART Moore RDand Chaisson RE. Ann Intern Med 1996;124:633–42.

  14. Non-Specific Presentation of MAC Gordin FM, et al. J Infect Dis 1997;176:126-32.

  15. Features Favoring MAC Over TB • Hepatosplenomegaly • Elevated alkaline phosphatase (> 2x ULN) • Elevated GGT (> 3x ULN) • Leukopenia • CAVEAT: Distinguishing between the 2 diagnoses may be complicated by epidemiologic factors Rolla V, et al. Rev Inst Med Trop Sao Paulo 1999;41:273–77.

  16. Diagnosis of Disseminated MAC • Recovery from a normally sterile body site • Mycobacterial blood cultures • >90% yield with 2 blood cultures • Growth typically occurs by day 14  DNA probe • Bone marrow biopsy rarely necessary • Positive culture from a stool or respiratory specimen indicates increased risk of disseminated disease, but is not diagnostic Spach D and Gallant J. HIV Web Study, University of Washington, 10/14/07. Accessed 8/31/12.

  17. Treatment Regimens • Macrolides achieve high intra-macrophage levels where MAC organisms are concentrated and ethambutol protects against development of resistance • Secondary prophylaxis may be discontinued CD4 >100 cells/mm3 for 6 months and they have completed 12 months of MAC therapy without ongoing clinical evidence of infection Kaplan J, et al. MMWR 2009;58(4):1-217.

  18. Case 2 • 30 yo male with no known medical history presented to the ED for dry cough and SOB • 2 ED visits for URI symptoms and coughin the preceding week • Recently relocated from AZ to MN • BP 116/56 | Pulse 106 | Temp36.8 °C | Resp24 | SpO2 93% • Appearsacutelydistressed

  19. What is the diagnostic test of choice? • Serum cryptococcal antigen • Sputum for AFB smear and culture • (1→3)-ß-D-glucanassay (Fungitell®) • Serum galactomannan (Aspergillus antigen) • Sputum for GMS staining • Serum coccidoidesantibodies

  20. It’s a Fungus! Cyst forms in GMS-stained BAL fluid Wright-Giemsa–stained trophic forms Calcofluor-stained fungal cell walls DFA of cysts

  21. Diagnostic Testing • Direct visualization required since organism cannot be cultured • Quick, widely available, but requires pathologist • GMS, Wright-Giemsa, calcofluor white • Induced sputum, tracheal aspirate, or BAL • Microscopy 50-90% sensitive in HIV patients • PCR  very sensitive; ?detect colonization Thomas and Limper. N Eng J Med 2004;350(24):2487-98.

  22. Clinical Pearls: HIV vs. Non-HIV Thomas and Limper. N Eng J Med 2004;350(24):2487-98.

  23. Treatment Options Thomas and Limper. Nat Rev Microbiol2007;5(4):298-308.

  24. Case 3 • 43 yo HIV-infected woman with a CD4 count of 22 cells/μlpresents with decreased vision in her left eye with new floaters. • She was diagnosed with HIV 1 year prior, but has not been engaged in care. She takes TMP-sulfa, but no other medications. • On examination, she has decreased visual acuity in her left eye. She is urgently referred to an ophthalmologist for evaluation of suspected cytomegalovirus (CMV) retinitis. Spach D and Chuang E. HIV Web Study, University of Washington, 10/14/07. Accessed 8/31/12.

  25. Which of the following is true? • CMV retinitis in HIV-infected patients usually results from reactivation disease due to previous infection. • In this situation, ART would be sufficient for treatment. • This patient had unusual presenting manifestations of CMV retinitis. Most patients present with eye pain, erythema, and vision loss. • The diagnosis of the CMV retinitis should be confirmed by use of PCR on vitreous fluid.

  26. CMV Basics • Retinitis is most common CMV manifestation • Major risk is CD4 count <50 cells/μl, but HIV RNA >100,000 copies/ml and concomitant MAC also risk • Reactivation of latent infection Spach D and Gallant J. HIV Web Study, University of Washington, 10/14/07. Accessed 8/31/12.

  27. 4 “F’s” of CMV Retinitis • Floaters • Flashes • Field deficits • Failing vision • Typically unilateral • No associated pain or redness • Diagnosed with dilated eye exam • Typically, no role for lab testing (serum or vitreous fluid)

  28. Intra-Ocular vs. Systemic Therapy Musch DC, et al. N Engl J Med1997;337:83-90. Martin DF, et al.N Engl J Med2002;346:1119-26. Spach D and Gallant J. HIV Web Study, University of Washington, 10/14/07. Accessed 8/31/12.

  29. Findings From CMV Retinitis Trials • Implant is more effective than intravenous ganciclovir for treating the affected eye • Implant alone is ineffective for prevention of contralateral involvement or extraocular disease • Implant plus oral ganciclovir is more effective than the implant alone for prevention of new CMV disease • Oral valganciclovir alone is at least as effective as IV ganciclovir Musch DC, et al. N Engl J Med1997;337:83-90. Martin DF, et al.N Engl J Med2002;346:1119-26. Spach D and Gallant J. HIV Web Study, University of Washington, 10/14/07. Accessed 8/31/12.

  30. Case 4 • 31 yo male immigrant from Guatemala presents with fever and new-onset seizure • Diagnosed with HIV/AIDS 3 months prior during hospitalization for Salmonella bacteremia • Has not taken any medications since discharge • BP 140/78| Pulse 90 | Temp37.8 °C | Resp18 | SpO2 99% • Exam notable for decreasedlevel of alertness and right-sidedweakness Spach D and Gallant J. HIV Web Study, University of Washington, 10/14/07. Accessed 8/31/12.

  31. Case 4 (cont.) • Blood cultures again grow Salmonella • Toxoplasma IgM negative; IgG positive • CT head with contrast shows multiple ring-enhancing lesions with surrounding vasogenic edema

  32. Which of the following is true? • The presence of >1 mass lesion rules out CNS lymphoma. • Approximately 10% of primary CNS lymphomas in patients with AIDS are EBV-associated. Performing CSF PCR does not provide additional information. • Based on the findings, primary CNS lymphoma is most likely and radiation therapy should be started. • Based on the findings, Toxoplasma encephalitis is most likely and therapy with pyrimethamine, sulfadiazine, and leucovorin should be started.

  33. Toxoplasma Basics • Protozoan parasite that infects humans as incidental hosts • Cats are definitive host (40% domestic cats, 60% stray cats seropositive for T. gondii) • Fecal-oral transmission or ingestion of undercooked meat • Primary infection: asymptomatic or mononucleosis-like

  34. Incidence of Toxoplasma Encephalitis, HIV Outpatient Study, 1994 – 2007 Buchacz K, et al. AIDS 2010;24:1549-59.

  35. Reactivation in HIV • Reactivation of latent organisms  symptomatic disease • 85% of HIV-infected persons with toxo have CD4 <100 cells/μl • Most common presentation is focal encephalitis – seizures, focal neurologic deficits • Uncommon presentations (1-2%): • Retinitis • Pneumonitis • Disseminated disease • Lifetime risk of developing toxo encephalitis in seropositive AIDS patient not on prophylaxis is 10-50% Richards FO Jr, et al. ClinInfect Dis1995;21 Suppl 1:S49-56.

  36. Clinical Approach Toxoplasma encephalitis Primary CNS lymphoma Negative toxo serology Appropriate use of prophylaxis Solitary brain lesion on MRI Positive CSF PCR for EBV • Positive IgG (~95% positive) • Non-use of prophylaxis • Multiple enhancing brain lesions in MRI • Positive CSF PCR for T. gondii • Empiric therapy recommended for multiple enhancing lesions • Brain biopsy reserved for non-response to therapy

  37. Time to Neurologic Response • Best-studied: • Pyrimethamine • Sulfadiazine • Leucovorin • Clindamycin may be substituted for sulfa (risk of relapse increases) • Corticosteroids? Luft BJ, et al. N Engl J Med 1993;329:995-1000.

  38. Prevention is Key • Early diagnosis and initiation of HAART • Immunizations • Annual influenza • 23-valent pneumococcal (baseline and q5 years) • Td/Tdap (q10 years) • Hepatitis A and/or B (if seronegative) • HPV based on age • Consider VZV and/or MMR as appropriate in HIV-infected persons with CD4 count >200 cells/μL Kaplan J, et al. MMWR 2009;58(4):1-217.

  39. Chemoprophylaxis Kaplan J, et al. MMWR 2009;58(4):1-217.

  40. Challenges in the U.S. • OI are still common • Late detection in some regions, urban and rural • Occurrence pre- and post-HAART • Considerable mortality attributable to OIs • Expertise in management may be waning • Early initiation of HAART is the best prevention

  41. Useful Resources • www.aidsinfo.nih.gov • HIV Treatment Guidelines for Adults and Adolescents • Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents • http://depts.washington.edu/hivaids/index.html • Web-based HIV case study

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