HIV-Associated Opportunistic Infections

1. HIV-Associated Opportunistic Infections Jonathan Vilasier Iralu, MD, FACP Indian Health Service Chief Clinical Consultant for Infectious Diseases

2. Case • A 29 year-old man has a history of AIDS with CD4 count of 67 and HIV Viral load of 19,000. He has a history of alcohol abuse and recurrent candida esophagitis. He comes to the office with a complaint of fever. Physical examination is notable for cachexia, a temperature of 101.2 degrees F and the absence of splenomegaly. Examination of the skin shows no abnormalities. A CT scan is obtained.

3. Case Presentation • What is the differential diagnosis for fever in this patient? • What should be done next?

4. HIV/AIDS Fever Differential Diagnosis • M. avium Bacteremia • Miliary Tuberculosis • Disseminated Pneumocystis • Cryptococcosis • Disseminated Coccidioidomycosis • Bacillary Angiomatosis • CMV • Non-Hodgkin’s Lymphoma

5. Fever Physical Exam • Adenopathy may suggest MAC, TB or lymphoma • Retinal lesions may suggest CMV • Umbilicated skin lesions suggest cryptococcosis • Purple-red raised nodules suggest bacillary angiomatosis

6. NAIHS HIV/AIDSInitial Fever Evaluation • CMP, CBC, CXR, Blood Cultures • Bactec Blood Culture • PPD skin test • Lumbar Puncture • Sputum induction for PCP and AFB • Dilated fundoscopic exam

7. NAIHS HIV/AIDSFever Evaluation continued • Abdominal CT • Bone Marrow • Consider: • Liver biopsy • Skin biopsy • Endoscopy

8. Case Presentation • The patient had negative blood cultures. He continued to deteriorate with worsening fever and cachexia. Splenectomy was performed which showed inflammatory cells and dilated capillaries. Warthin Starry stain showed organisms consistent with Bartonella. A Bartonella henselae antibody test came back positive.

9. Bartonellosis in HIV: History • First described by Stoler et al in 1983 • Pathology showed tiny gram negative rods with vascular proliferation. • Named Bacillary Angiomatosis by Le Boit et al in 1988.

10. Bartonellosis in HIV: Epidemiology • Two Species • Bartonella henselae: • Cat Scratch Disease • cat flea association • More likely to involve the liver and spleen • Bartonella quintana • Trench Fever • Associated with homelessness and the human louse • More likely to involve bone

11. Bartonellosis in HIV: Clinical Presentation • Symptoms: • Fever • chills • night sweats • malaise • headache • anorexia

12. Bartonellosis in HIV: Clinical Presentation • Sites of infection: • Cutaneous: Violaceous, raised papules that bleed like KS • Osteolytic bone lesions: painful lesions, positive bone scan • Brain: Brain abscess with seizures • Lymphadenitis • Endobronchial/laryngeal obstructing polypoid masses • Bacteremia/Endocarditis

13. Bartonellosis in HIV: Clinical Presentation • Liver: Peliosis hepatitis/Splenitis: • blood filled cystic lesions • alkaline phosphatase usually elevated , up to 10-fold • pancytopenia

14. Bartonellosis in HIV: Microbiology • Small fastidious Gram-Negative Rod • Culture blood using Isolator Tubes (Wampole) • Culture material on Chocolate or Heart Infusion agar • Require CO2, 35-37 degree C temp, and 21 days incubation

15. Bartonellosis in HIV: Pathology • Pathology: • Vascular proliferation with thickened endothelium. • Warthin-Starry Silver Stain: • Small organisms in the endothelium

16. Bartonellosis in HIV: Diagnosis • Microbiology • Pathology • Serology- IFA IgG titer • <1:64 past infection • 1:64-1:256 posible infection • >1:256 diagnostic

17. Bartonellosis in HIV: Treatment • Erythromycin 500 mg po qid f or Doxycycline 100 mg po bid • Lifelong suppression may be needed • Immune reconstitution inflammatory syndrome not reported.

18. Case Presentation • A 42 year-old man is referred to ID clinic with a positive PPD at 10 mm after being exposed to a case of active pulmonary TB. He has a history of reactive arthritis but is not on immunosuppresive therapy. Review of symptoms is completly negative and physical exam is unremarkable. A CXR is normal. He is offered Isoniazid therapy but declines.

19. Case Presentation • Nine months later the patient presents with chronic cough and fever. On exam he is tachycardic and diffuse rales. A CXR is obtained…

20. HIV Pulmonary Infiltrate Differential • Bacterial pneumonia • Tuberculosis • M kansasii • Pneumocystis • Toxoplasmosis • Cryptococcosis • Coccidioidomycosis • Blastomycosis • Aspergillosis • Strongyloidiasis • CMV • VZV • Kaposi’s Sarcoma • Lymphoma • Lymphocytic Interstitial Pneumonitis

21. Initial evaluation of infiltrates • Routine Gram stain and culture • Blood cultures • Sputum AFB smear and culture X 3 • Induced sputum for PCP immunofluorescence

22. HIV Pulmonary Infiltrate Therapy • Typical pneumonia, high CD4 count • Third generation cephalosporin plus a macrolide • Atypical pneumonia, low CD4 count • Trimethoprim/Sulfa plus a cephalosporin plus a macrolide

23. HIV: Further Infiltrate evaluation • What to do next if routine tests are negative • Bronchoalveolar Lavage • Transbronchial lung biopsy • Transcutaneous lung biopsy

24. Case Presentation • The patient is admitted and treated empirically for bacterial pneumonia with Ceftriaxone/Azithromycin and for Pneumocystis jiroveciwith Trimethoprim/Sulfa. Sputa are induced for AFB and the smears are positive. The CD4 count comes back at 197. The patient is started on INH,Rifampin,pyrazinamide and ethambutal. Tenofovir, Emtricitabine and Efavirenz are started 2 weeks later. Cultures grow Mycobacterium tuberculosis

25. Case Presentation • The patient has a rapid improvement in his fevers and cough. One month later in clinic he notes worsening cough and exam reveals low grade fever and bronchial breath sounds. A F/U CXR shows a new cavity in the right mid lung zone.

26. HIV and TuberculosisEpidemiology • 2010 worldwide • 34 million people living with HIV • 8.8 new cases of tuberculosis • 1.1 million of the new cases also had HIV • 350,000 HIV patients died of TB • HIV increases the RR of TB infection by 20 to 30 -fold

27. TB/HIV Clinical Presentation • TB in early HIV behaves like HIV (-) disease • Cough • Hemoptysis • Fever • Night sweats • Weight loss • Upper lobe pulmonary disease with cavitation

28. TB/HIV Clinical Presentation • TB in late HIV disease is different • Looks like primary TB • Lymphadenopathy present on exam and CXR • Miliary pattern • Cavitation is less frequent • Extrapulmonary sites involved in 40-80%: • Lymph nodes, brain, meninges, pericardium, abdomen

29. TB/HIV Clinical Presentation • Subclinical TB disease is common in HIV • Smear negative disease is more common in HIV • 22% of patients with HIV and TB have a normal CXR

30. Diagnosis of TB • Sputum AFB x 3 in 24 hours including one early AM • 2 sputa may be adequate— “Front loading” (Yassin et al) • Culture • BACTEC and MGIT technology • Nucleic Acid Amplification • CDC recommends sending one on every patient • Xpert MTB/RIF assay recently approved by FDA in July 2013

31. Treatment of TB in HIV • Latent TB • Diagnosis with PPD or IGRA (quantiFERON assay) • Rule out active TB first • Treat with INH for 9 months

32. Treatment of TB in HIV • Active TB • Treat the TB with INH/Rifampin/Pyrazinamide/Ethambutal • Rifampin is the key agent • Rifabutin is substituted if the patient is already on a protease inhibitor • Treat the treatment naïve patient with HIV with Tenofovir/Emtricitabine/Efavirenz (Atripla) if at all possible • Consider and increase in efavirenz dose if weight > 60kg

33. Drug interactions • Rifampin lowers the drug levels of cyp3a4 metabolized drugs including efavirenz, protease and integrase inhibitors . • Rifabutin metabolism is inhibited by ritonavir • Dose cut 50% and given thrice weekly • If you need assistance…

34. Immune Reconstitution Inflammatory Syndrome • Re-awakening immune syndrome unmasks or causes paradoxical disease: • Cryptococcal meningitis • PML (JC virus) • PCP • CMV retinitis/gastroenteritis • Tb and MAC • Risk Factors: low CD4, high viral load, HLA -44

35. Immune Reconstitution Inflammatory Syndrome • Two TB syndromes: • Subclinical TB is unmasked after anti HIV therapy is started • Fever, adenopathy, pulmonary, neurologic symptoms • Paradoxical worsening of pre-existing TB after starting ARVs • New cavitation • Hypercalcemia is a hallmark. • Can occur even in HIV negative patients with anti Tb therapy

36. Immune Reconstitution Inflammatory Syndrome • Prevention • Start TB therapy right away • Delay start of HIV Therapy • CD4 count < 50  Start antiretrovirals by < 2 weeks • CD4 count > 50  Start antiretrovirals by 8-12 weeks • Treatment • NSAIDS • Steroids

37. HIV/AIDS UpdateCase • A 53 year old woman with HIV now has diarrhea. She was treated with ZDV/3TC/NFV originally but now is on a second regimen including TDF/FTC/ATZ/rtv. She notes 6 weeks of watery stools without fever or blood • What is the differential diagnosis? • What should you do now?

38. NAIHS HIV/AIDSDiarrhea • Chronic • CMV • Microsporidia • Cryptosporidia • MAC • Isospora • Cyclospora • Giardia • Acute • Shigella • Salmonella • Campylobacter • C. Difficile

39. NAIHS HIV/AIDSDiarrhea • Bloody • Shigella • Salmonella • Campylobacter • C. difficile • CMV • Entamoeba • Watery • Microsporidia • Cryptosporidia • MAC • Isospora • Giardia • Entamoeba • Cyclospora

40. NAIHS HIV/AIDSDiarrhea work up • Initial evaluation • CBC, electrolytes, BUN, Creatinine, LFTS • Routine stool culture • Clostridium difficile toxin assay • Stool Ova and Parasites exam • Stool Trichrome stain • Stool Modified AFB Stain

41. NAIHS HIV/AIDSDiarrhea workup • Further workup • Upper endoscopy with small bowel Bx. • Colonoscopy with Bx.

42. Microsporidiosis • Spore forming protozoan with fungal characteristics • Ubiquitous in the environment • 1-2 microns in size • Two species • Enterocytozoan bieuneusi- major cause of diarrhea • Encephalitozoan cuniculi and hellem- disseminate • Distort small bowel villous architecture

43. Microsporidiosis • Clinical syndrome: • Profuse watery diarrhea • Median CD4 is 20 • Biliary, lung, corneal, renal disease and encephalitis all occur • Diagnosis • Modified trichrome stain

44. Microsporidiosis • Treatment • Albendazole 400 mg po bid for Encephalocytozoan sp • No reliable Rx for Enterocytozoan bienusi

45. Cytomegalovirus colitis • CMV is a herpesvirus that infects latently • AIDS patients affected when CD4 <50 • CMV viremia is a risk factor for subsequent invasion

46. Cytomegalovirus • Clinical Manifestations • Esophagitis with odynophagia, fever and nausea • Gastritis with epigastric pain but rarely bleeds • Enteritis of small bowel: pain and diarrhea • Colitis: fever, weight loss, watery diarrhea and hemorrhage

47. Cytomegalovirus colitis • Diagnosis: • PCR of blood • Biopsy: cytomegalic cells with eosinophilic intranuclear and basophilic cytoplasmic inclusions.

48. CMV Treatment • Gancylovirinduction 5 mg/kg IV q 12 hrs then Valgancyclovir 900 mg po bid when better for 3-6 weeks • Maintenance therapy with daily VGC for relapsed cases • Support WBC with G-CSF • Foscarnet is usually reserved for salvage therapy

49. Case presentation • A 51 year old man with HIV develops sudden visual impairment in the right eye. He has had low grade fevers for a few weeks. His last CD4 count was 97 and the viral load is > 100,000.

50. CMV Retinitis • Affect 47% of patients with CD4 < 50 • If no HAART is given, median time to progression is 47-104 days. • Median time to death was 0.65 years in the pre HAART era.