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February 11, 2010 HIV-Associated Opportunistic Infections 2010 Robert D. Harrington, MD

February 11, 2010 HIV-Associated Opportunistic Infections 2010 Robert D. Harrington, MD. HIV-Associated Opportunistic Infections 2010. Robert D. Harrington, M.D. University of Washington. MMWR 1981. CD4 Count and Opportunistic Infections. CD4 Cell Count. Bacterial Pneumonia, TB,

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February 11, 2010 HIV-Associated Opportunistic Infections 2010 Robert D. Harrington, MD

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  1. February 11, 2010 HIV-Associated Opportunistic Infections 2010 Robert D. Harrington, MD

  2. HIV-Associated Opportunistic Infections 2010 Robert D. Harrington, M.D. University of Washington

  3. MMWR 1981

  4. CD4 Count and Opportunistic Infections CD4 Cell Count Bacterial Pneumonia, TB, HSV, Cryptosporidiosis 1,000 Thrush, lymphoma, KS 500 PCP 200 100 MAC, CMV, PML, PCNSL, Cryptococcus, Microsporidia Toxo 4-8 Weeks Up to 12 Years 2-3 Years

  5. Common OIs PCP MAC Candida Regional Effects Southwest: Coccidiodomycosis Midwest: Histoplasmosis and Blastomycosis South: Blastomycosis and Toxoplasmosis Opportunistic Infections and Geography North America

  6. Opportunistic Infections and Geography PCP, TB Candida, MAC Cryptococcus Leishmaniasis The World PCP TB Candida Cryptococcus Penicilliosis Candida PCP MAC TB Bacteria Malaria Cryptococcus PCP TB Cryptococcus Isospora Cryptosporidiosis Microsporidia Holmes, CID, 03 Putong, SEA Trop Med, 02 Margues, Med Mycol, 2000 Amornkul, CID, 03

  7. PCP MAC Cryptosporidiosis Microsporidiosis Bacterial respiratory infections Bacterial enteric infections Bartonellosis Coccidiodomycosis Paracoccidiomycosis Histoplasmosis Cryptococcus Toxoplasmosis Candida TB Aspergillosis CMV HSV VZV PML (JCV) HHV-8 HPV Penicilliosis Leshmaniasis HIV-Associated and Opportunistic Infections

  8. HIV ASSOCIATED MALIGNANCIES AIDS Defining Malignancies • Kaposi’s sarcoma • Primary CNS lymphoma (PCNSL) • Non-Hodgkin’s lymphoma (NHL) • Invasive cervical cancer

  9. Hodgkin’s disease Anal cancer Multiple myeloma Leukemia Lung cancer Head and neck tumors GI malignancies Genital cancers Hypernephroma Soft tissue tumors HIV ASSOCIATED MALIGNANCIES Increased Rates of Other Cancers in HIV

  10. Prophylaxis to Prevent Opportunistic Infections Considerations for Prophylaxis • Infection should be common and/or predictable • Infection should be clinically significant • Treatment (prophylaxis) should be effective, non-toxic and affordable

  11. Prophylaxis to Prevent Opportunistic Infections in the Developed World Primary Prophylaxis PCP CD4 < 200 TMP/SMX MTb PPD > 5mm INH Toxo IgG+, CD4 < 100 TMP/SMX MAC CD4 < 50 Azithromycin VZV Vaccine S. Pneumoniae Vaccine HBV Vaccine HAV Vaccine Influenza Vaccine

  12. Cotrimoxazole is beneficial in all pts with HIV infection regardless of CD4 count • Study in rural Uganda enrolled 509 HIV+ & 1522 HIV- individuals • All clients observed for 5 months after which HIV+ were given TMP-SMX (960mg) and followed up for 1.5yrs Mermin et al. Lancet 2004 ; 364: 1428

  13. Outcomes on Cotrimoxazole Prophylaxis • Mortality reduced by 46%, p=0.006 • Malaria incidence reduced by 72% p<0.0001 • Diarrhea incidence reduced by 35% p<0.0001 • Clinic visits reduced by 15% p=0.04 • Hospital admissions reduced by 21% p=0.04 Mermin et al. Lancet 2004 ; 364: 1428

  14. Cotrimoxazole WHO. Guidelines on co-trimoxazole prophylaxis for HIV-related infections among children, adolescents and adults. 2006

  15. WHO Guidelines 2008: Prophylaxis to Prevent Opportunistic Infections in the Resource-limited settings

  16. WHO Guidelines 2008: Prophylaxis to Prevent Opportunistic Infections in the Resource-limited settings

  17. EFFECTS OF HAART ON OPPORTUNISTIC INFECTIONS • Declining incidence • Reduced need for prophylaxis (primary and secondary) • Spontaneous improvements and cure • Immune reconstitution effects

  18. Case 1 • A 32 yo HIV+, pregnant Ugandan woman who has been living in South Africa since she was 12 decides to return to Uganda to celebrate her mother’s 50th birthday. • A week after arriving she develops fever, myalgias, headache, mild dyspnea and diarrhea. She takes Tylenol for her fevers with little effect and then becomes lethargic over the next 12 hours prompting her family to bring her to the local clinic. • PMHx notable for HIV (untreated with CD4 of 189), thrush and 2 previous spontaneous abortions

  19. Case 1 • On exam she is obtunded but is arousable. VS: BP 100/60, HR 115, T 39.0, RR 14. Conjunctiva are pale, oral exam shows white plaques, lung exam reveals fine rales at the bases, CV RRR with 2/6 SEM, ABD is soft and non tender, skin is clear • What are some diagnostic possibilities? • Malaria • Meningitis (bacterial, cryptococcal > TB) • Bacteremia (Salmonella, S pneumonia, N. meningititis) • Pneumonia (bacterial, PCP) • Typhoid fever or enteritis

  20. Case 1 • What diagnostic testing do you want: • CBC and chemistries: Hct 28, WBC 6, plts 90K, glucose 70, creat 1.4 • Blood cultures for bacteria, AFB and fungi: done and pending • CRAG: negative • CSF exam: RBC 0, WBC 8 (all lymphs), glucose 60, protein 30, CRAG negative, Gram’s stain negative • CXR - normal • Blood smear

  21. Case 1 (Malaria.org.za)

  22. Malaria: Epidemiology • 300 to 500 million cases per year • 1 million deaths per year • 80% in African children • Geographic overlap with HIV epidemic

  23. Malaria: Epidemiology Overlapping geography, although: Malaria mostly rural HIV mostly urban WHO, 2006

  24. HIV/Malaria Interaction • Modeling suggests that HIV leads to additional 3 million cases of malaria and additional 65,000 malarial deaths (Korenromp, Emer Inf Dis, 2005) • Malaria is associated with increased in HIV RNA: increase of 0.25 log with asymptomatic infection and 0.89 log with symptomatic malaria (Kubin, Lancet, 2005)

  25. HIV/Malaria Interactions (Slutsker, Curr Opin Infec Dis, 2007)

  26. Case 1 Why did this patient become so ill?

  27. HIV/Malaria: Clinical Presentation Severity Risks • Residence in a malaria endemic region? • Yes: Adults mostly immune, disease primarily in children < 5 • No: Population not immune – more severe disease • Pregnancy • Even if residing in endemic region – reduced immunity

  28. HIV/Malaria: Clinical Presentation Severity Risks • HIV status • Increased frequency of malaria (clinical and subclinical) • Increased severity - especially in those with CD4 < 200 • Higher parasite densities and more clinical symptoms with lower CD4 counts (Grimwade, AIDS, 2004) (Patnaik, JID, 2005) (Cohen, CID, 2005) (Whitworth, Lancet, 2000)

  29. HIV/Malaria: Clinical Presentation • Prospective cohort study in Chris Hani Baragwanath Hosptial in Soweto, SA • N=336; 33% HIV+, 33% non-immune • Risks for severe disease: HIV+ status, high parasite load, and high WBC • HIV patients: • Risk of severe disease higher in those with CD4 < 200 • Risk of severe disease higher only in non-immune patients (OR 4.15) • More atypical symptoms (GI and respiratory) (Cohen, CID, 2005)

  30. HIV/Malaria: Clinical Presentation Clinical Signs and Symptoms • Non-immune patients • Fever (q48 for all but P. malariae, q72), chills, myalgia, headache, vomiting, diarrhea, splenomegaly, thrombocytopenia, pulmonary and renal dysfunction, • Severe disease: acidosis, hypoglycemia, DIC, shock, cerebral malaria (40% mortality in Africa)

  31. HIV/Malaria: Diagnosis • Blood smear • Antigen detection methods • PCR • Non-immune patients may have symptoms prior to detectible parasitemia – need to perform serial testing

  32. HIV/Malaria: Prevention • How might her infection have been averted? • If she hadn’t gone home! • Chemo-prophylaxis • Insecticide treated nets

  33. HIV/Malaria: Prevention • Prospective cohort study of 1035 patients that were given TMP/SMX (TS) or TS + ARV or TS + ARV + ITN (interventions added to population over time) • Compared with baseline malaria incidence rate of 50.8/100py • TS = 9/100py • TS/ARV = 3.5/100py • TS/ARV/ITN = 2.1/100py (Mermin, Lancet, 2006)

  34. HIV/Malaria: Prevention Malaria Prevention in HIV+ Pregnant Women (Brentlinger, Behrens, Micek, Lancet ID, 2006)

  35. HIV/Malaria: Treatment • Dictated by • Malaria species • Clinical status • Regional drug susceptibilities

  36. HIV/Malaria: Treatment • P,O study of SP therapy for malaria in patients presenting to clinic at Siaya District Hospital, Kenya (2002-04) • N=508, 130 HIV-, 256 HIV+ with CD4 > 200 and 122 HIV+ with CD4 < 200. All treated with SP (1500/75) • MV analysis looking at treatment failure at 28 days. Compared to HIV- patients: HIV+ patients with anemia had a significantly higher failure rate (20.5% Vs 7.7% - HR of 3.4)

  37. HIV/Malaria: Treatment http://www.cdc.gov/malaria/pdf/treatmenttable.pdf

  38. HIV/Malaria: Treatment http://www.cdc.gov/malaria/pdf/treatmenttable.pdf

  39. HIV/Malaria: Treatment http://www.cdc.gov/malaria/pdf/treatmenttable.pdf

  40. HIV/Malaria: Treatment http://www.cdc.gov/malaria/pdf/treatmenttable.pdf

  41. HIV/Malaria: Treatment/Drug Interactions (Khoo, AIDS, 2005)

  42. HIV/Malaria: Treatment/Drug Interactions • Quinine is extensively metabolized by CYP 3A4. Quinine exposure may be increased in patients on PIs (RTV) and decreased in patients on NNRTI (EFV, NVP, ETV) • Lumefantrine and halofantrine are extensively metabolized by CYP 3A4 and halofantrine can prolong the QT interval. Using either drug in patients on PIs should be avoided. NNRTI use would be expected to decrease exposure to these drugs (Khoo, AIDS, 2005)

  43. Case 2 • A 32 yo HIV+ male with a CD4 of 12 presents with fever, headache and confusion for 2 days. He complained to his partner of blurred vision from his R eye 1 day PTA. • PMHx is notable for thrush, esophageal candida, wasting syndrome, chronic HBV and HCV, several episodes of zoster (the most recent a month ago) and active IVDU

  44. Case 2 • On exam he is obtunded but arousable. T 39, HR 110, BP 110/70, RR 14. R pupil reacts poorly to light. No meningismus. Lungs are clear, CV: RRR, 2/6 SEM at the base of the heart, no gallops, Abd: quiet BT, mild RUQ tenderness, Skin: multiple injection tracks, scars at sites of previous skin abscesses and zoster outbreaks.

  45. Case 2 • What diagnoses are you considering • ABE with emboli • Toxoplasmosis • Cryptococcal meningitis • Bacterial meningitis • CMV • VZV

  46. Case 2 • What diagnostic testing do you want • BC: done and pending • CRAG: negative • CMV PCR from plasma: 100 copies • CSF exam: RBC 2, WBC 15 (lymphs), protein 60, glucose 50, Gram’s stain negative, CRAG negative, PCR for CMV negative, EBV 80 copies, HSV negative, VZV 110 copies

  47. Case 2 Brain MRI (www.medscape.com)

  48. Case 2 Dilated Eye Exam

  49. Case 2 Diagnosis? • VZV encephalitis and RPHRN

  50. Varicella-zoster virus • Organism: Varicella-zoster virus, a member of the herpes virus family. • Epidemiology: • In the pre-vaccine era over 90% of US adults were sero-positive for VZV. • Risk of developing zoster in HIV infected individuals is 17 times that of non-infected patients (~30/1000 py in HIV+ men Vs 2/1000 py in HIV- men). • Recurrent attacks in HIV+ patients: ~20-30%. (Rogues, JID, 1993) (Veenstra, AIDS, 1995)

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