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Opportunistic Infections Dr. Robert Harrington, M.D. December 18, 2008

Opportunistic Infections Dr. Robert Harrington, M.D. December 18, 2008. MMWR 1981. HIV Infection: Pathogenesis. Typical Course. Sero-conversion Antibody response. Anti-HIV T-cell response. Intermediate Stage. AIDS. CD4 Cell Count. Plasma RNA Copies. Viral set point. 1,000.

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Opportunistic Infections Dr. Robert Harrington, M.D. December 18, 2008

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  1. Opportunistic Infections Dr. Robert Harrington, M.D. December 18, 2008

  2. MMWR 1981

  3. HIV Infection: Pathogenesis Typical Course Sero-conversion Antibody response Anti-HIV T-cell response Intermediate Stage AIDS CD4 Cell Count Plasma RNA Copies Viral set point 1,000 CD4 Cells 500 4-8 Weeks Up to 12 Years 2-3 Years A lot of important stuff happens here

  4. CD4 Count and Opportunistic Infections CD4 Cell Count Bacterial Pneumonia, TB, HSV, Cryptosporidiosis 1,000 Thrush, lymphoma, KS 500 200 PCP 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. 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

  8. Primary PCP CD4 < 200 MTb PPD > 5mm Toxo IgG+,CD4 < 100 MAC CD4 < 50 VZV Exposure with IgG- or no hstry S. pneumoniae HBV HAV Influenza Secondary PCP Toxo MAC CMV Cryptococcosis Histoplasmosis Coccidioidomycosis Salmonella species bacteremia Recurrent HSV Recurrent Candidiasis Prophylaxis to Prevent Opportunistic Infections in the Developed World

  9. Prophylaxis to Prevent Opportunistic Infections in the Developing World Primary prophylaxis: Secondary prophylaxis: for PCP and Cryptococcus WHO Guidelines on co-trimoxazole prophylaxis for HIV-related infections among children, adolescents and adults. August, 2006

  10. TB prevention • WHO recommendation: • Treat tuberculin skin test positive HIV-infected persons without active TB with 6 month regimen isoniazid preventive therapy (IPT) • Difficulties: • Lack of tuberculin skin testing • People not screened • Screen positive do not receive INH • Screen positive started on INH do not complete regimen

  11. 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

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

  13. 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

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

  15. EFFECT OF HAART ON INCIDENCE OF OPPORTUNISTIC INFECTIONS J.E. Kaplan et al. CID 2000;30:S5-S14 (Kovacks, NEJM, 2000)

  16. Effect of HAART on Opportunistic Infections: Reduced Need for Prophylaxis Primary Prophylaxis PCP When CD4 > 200 for 3 months MAC When CD4 > 100 for 3 months Toxo When CD4 > 200 for 3 months

  17. Effect of HAART on Opportunistic Infections: Reduced Need for Prophylaxis Secondary Prophylaxis or Maintenance Therapy PCP When CD4 > 200 for 3 months CMV When CD4 > 100-150 for 6 months MAC When CD4 > 100 for 6 months, no symptoms of MAC and after 12 months of MAC Rx Toxo When CD4 > 200 for 6 months and completed initial Toxo Rx Cryptococcus When CD4 > 100-200 for 6 months and completed initial Crypto Rx

  18. Opportunistic Infections Treatable with HAART alone • Progressive Multifocal Leukoencephalopathy (PML) • Cryptosporidiosis • Microsporidiosis • Kaposi’s sarcoma • Mycobacterium avium complex (sometimes)

  19. Case 1 • A 40 yo male with severe bipolar disease presents with cough, weight loss, dyspnea and low grade fever. • His PMH is notable for recurrent bacterial pneumonia, methamphetamine and alcohol abuse. He has refused all medications. • On exam he is thin and in mild respiratory distress. T 38C, BP 100/70, HR 100, RR 18, O2 saturation 89% at rest. Lung exam reveals fine rales at lung bases.

  20. Case 1 CXR of Case 1 (www.learningradiology.com)

  21. Case 1 • What diagnostic studies do you want? (www.tulane.edu)

  22. Case 1 • Treatment: • TMP-SMX, pentamidine • Timethoprim-dapsone, clindamycin and primaquine, atovoqone • Trimetrexate and leucovorin • Severe disease (paO2 < 70 or Aa gradient > 35): add steroids How would you treat this patient?

  23. Case 1 • Over the next 10 days the patient slowly improves. • His CD4 T-cell count returns at 60 cells/uL. • Should he receive HAART and, if so, when should he start?

  24. Timing of HAART #142: Immediate Vs Delayed ART in Setting of Acute OI, Zolopa, Powderly, et.al. (ACTG 5164) • Randomized study of ARV given within 14 days of Rx for OI Vs delayed (at least 4 wks) • Patients with TB excluded • Primary endpoint: 48 week combination of 3 categorical variables • 1. Death or alive with new AIDS diagnosis • 2. Alive with HIV RNA > 50 and no new AIDS diagnosis • 3. Alive with HIV RNA < 50 and no new AIDS diagnosis

  25. Timing of HAART #142: Immediate Vs Delayed ART in Setting of Acute OI, Zolopa, Powderly, et.al. (ACTG 5164) • Patients (N=282) • Median age 38 • Median CD4 = 29 and log10 HIV RNA level = 5.07 • OIs • PCP 63% • Cryptococcal meningitis 13% • Pneumonia 10% • Median time to starting ART 12 Vs 45 days

  26. Timing of HAART ACTG 5164: Results • No significant difference between immediate Vs delayed for the composite endpoint • Immediate arm had fewer deaths/new AIDS diagnosis • Immediate arm had longer time to death/new AIDS diagnosis (HR 0.53) P=0.035

  27. Case 2 • RT is an asymptomatic 47 yo Asian male with newly diagnosed HIV who presents for care. • His PMH is notable for multiple STDs and “hepatitis” • PE is notable only for thrush, mild cervical adenopathy and seborrheic dermatitis. • CD4 is 380, HIVRNA is 80K, ALT is 240, HepAAB+, HepCAB and RNA negative, HepBsAG+, cAB+, eAG+ and HBV DNA 40 million

  28. Case 2 • How common is chronic Hepatitis B infection and why do you suppose he has it? • What about co-infection with HIV?

  29. Outcome of Hepatitis B by Age of Acquisition 100 100 80 80 60 60 Chronic Infection (%) Chronic Infection Symptomatic Infection (%) 40 40 20 20 Symptomatic Infection 0 0 1-6 months 7-12 months Older Children and Adults Birth 1-4 years Age at Infection

  30. Natural History: Acute HBV Infection with Progression to Chronic Infection Acute (6 months) Chronic (Years) HBeAg anti-HBe HBsAg Total anti-HBc Titer IgM anti-HBc Weeks after Exposure Years 0 4 8 16 20 24 28 36 12 32 52

  31. Natural History: Chronic HBV Definitions: NIH Workshop Perinatal Transmission Horizontal Transmission 60-80% Immune Active (Clearance) Inactive Chronic Carrier Immune Tolerant 20-40% (Hoofnagle, Hepatology 2007;45:1056-1075)

  32. Natural History: Chronic HBV Definitions: NIH Workshop • HBsAg-positive for at least 6 months • Phases of Chronic hepatitis B • Immune Tolerant Phase: HBeAg+, normal ALT, HBV DNA > 200,000 IU/ml (>1 million copies) • Immune Active or Clearance Phase: elevated ALT, HBV DNA > 2,000 IU/ml, HBeAg or anti-HBe • Inactive Hepatitis B carrier: anti-HBe, ALT WNL, HBV DNA < 2,000 IU/ml • Reactivation of hepatitis • Clearance of HBsAg (Hoofnagle, Hepatology 2007;45:1056-1075)

  33. Hepatitis B: Epidemiology • 2 billion people have evidence of HBV infection • 1/3 of world’s populations • 350 million people chronically infected • 15% to 25% will develop HBV-related chronic liver disease (cirrhosis, hepatocellular carcinoma) and die without intervention • Up to 1 million deaths worldwide each year from HBV-related chronic liver disease

  34. Hepatitis B: Epidemiology HBsAg Prevalence 8% - High 2-7% - Intermediate <2% - Low

  35. Hepatitis B: Epidemiology • Among all the chronic hepatitis B carriers worldwide, 75% are Asians • While the overall incidence of chronic hepatitis B in the US population is less than 1 in 200, the incidence among Asian Americans is 1 in 10 (Source: Asian Liver Center of Stanford University) • 9-16% of HIV infected patients in the US are co-infected with HBV

  36. Case 2 ….back to the case • He is not inclined to start HAART but wants to discuss it with you. • Should you be worried about his HBV infection and why? • Does it influence your decision to recommend HAART?

  37. Natural History: Long-Term Outcome of Chronic HBV • Hepatocellular carcinoma (HCC) • 25%-40% of males • 10-15% females • Cirrhosis • 10% to 20% of males and females Beasley. Cancer 1988;61:1942-66 McMahon. Ann Intern Med 2001;135:759-768

  38. Elevated HBV DNA as Risk for HCC: R.E.V.E.A.L.-HBV Study* • 23,820 residents 7 townships in Taiwan • 4,155 HBsAg-positive • 3,653 tested for HBV DNA at entry • Median age 46 years; follow-up 11.4 years • Findings: Risk factors for HCC at study entry using Regression analysis • HBV DNA > 104 copies/ml • Liver cirrhosis • Age APPLIES TO ADULTS > 40 WITH GENOTYPES B&C Chen, C.-J. et al. JAMA 2006;295:65-73. Chen JAMA 2006;295:65-73 *Funded by Bristol Myers Squib

  39. Cumulative Incidence of Hepatocellular Carcinoma by Serum HBV DNA Level at Study Entry Chen, C.-J. et al. JAMA 2006;295:65-73.

  40. Natural History: Chronic HBV: Factors Associated with Progression • HBV • HBV DNA level • Genotype • Pre-core mutant • Core Promoter mutations • Other viruses: HIV, DELTA, HCV • Demographic: Age, male sex • Environmental and Social • Alcohol • NAFLD • Aflatoxin

  41. Natural History: Chronic HBV/HIV Co-infection • Co-infected patients have • Higher HBV DNA levels • Lower rates of spontaneous HBeAg clearance • More severe liver disease and higher liver-related mortality • May experience severe hepatitis flares due to immune reconstitution after HAART • May have “occult” HBV infection with high HBV DNA levels but with negative HBsAg. • Any HIV+ patient who tests + for either HBsAg or HBcAB should be tested for HBV DNA

  42. Long-Term Goals of Antiviral Therapy • Decrease risk of development of cirrhosis • If cirrhosis is present, decrease risk of decompensation • If decompensated cirrhosis present, treat to revert patient to compensated cirrhosis • Decrease risk of development of hepatocellular carcinoma

  43. AASLD Practice Guidelines, 2007* HBsAg + HBeAg Positive ALT < 1 X ULN ALT 1-2 X ULN ALT >2 X ULN Q 3 mo ALT Q 6 mo HBeAg Liver bx if persistent or age > 40, Rx as needed Q 1-3 mo ALT, HBeAg If persistent, Liver bx & Rx; Immediate Rx if jaundice or decompensated Q 6 mo ALT Q 12 mo HBeAg • Lok & McMahon. Hepatology 2007;45:507-539. Available at aasld.org * HCC surveillance if indicated

  44. AASLD Practice Guidelines, 2007* HBsAg + HBeAg Negative ALT > 2X ULN DNA > 20,000 IU/mL ALT 1-2X ULN DNA 2,000-20,000 IU/ml ALT < 1X ULN DNA < 2,000 IU/mL Q 3 mo ALT & DNA If results persist, liver bx, treat as needed Q 3 mo ALT X 3, Then Q 6-12 mo If ALT still WNL Liver bx & Rx • Lok & McMahon. Hepatology 2007;45:507-539. Available at aasld.org * HCC surveillance if indicated

  45. Treatment of HBV/HIV Co-infection • All HBV/HIV patients should be offered HAART • If treating HBV only can use IFN or adefovir • When treating both HIV and HBV - Rx with TDF and FTC is preferred • Patients already on HAART with agents not active against HBV can be treated with the addition of IFN, adefovir or entecavir • Patients with lamivudine resistant HBV can be treated with the addition of TDF • When altering HAART, consider the need to continue HBV therapy unless the patient has cleared HBeAg

  46. Case 3 • A 38 yo South African male presents with a 10 kg weight loss, 10 weeks of cough and intermittent fever. He has no past medical history. • On exam he is thin, T 38.8 C, BP 100/70, HR 104, RR 20. He has prominent cervical adenopathy, oral thrush and course breath sounds over his R upper and mid lung zones.

  47. Case 3 What diagnostic testing do you want? • HIV test is + and Sputum smear stains 3+ for AFB

  48. Case 3 • He is admitted to a hospital ward with similar patients and started on “RIPE” therapy. • After a week his constitutional symptoms improve. His CD4 T-cell count measures 15 cells/uL. • Should he be offered HAART? • If so, when should HAART be started? • Are there TB and HIV drug interactions of concern?

  49. WHO/DHHS: Treatment HIV-TB Pulmonary TB Extrapulmonary TB CD4 < 100 Start TB therapy, start HAART in 2 weeks Start TB therapy HAART as soon as TB Rx tolerated (b/n 2-8 wks) Some experts would wait until 8 weeks (avoid IRIS) CD4 100-200 Start TB therapy HAART after intensive phase of TB Rx (HAART earlier if severely immunocompromised) CD4 200-350 Start TB therapy Monitor CD4 count and start HAART when indicated CD4 > 350 CD4 not available TB therapy Improving, no OIs HAART when TB Rx complete

  50. Treatment and Outcome Survival Thailand • Retrospective study of 1103 HIV+ patients with TB • 411 received HAART • Risk factors for death • No HAART • Delay of HAART > 6 months • MDR TB • Gastrointestinal TB (Manosuthi, J Acquir Immune Defic Syndr 2006;43:42-46)

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