1. 1 Overview of Opportunistic Infections in HIV/AIDS HAIVN Harvard Medical School AIDS Initiative in Vietnam

2. 2 Learning Objectives By the end of this session, participants should be able to: Explain the relationship between CD4 count and incidence of specific opportunistic infections (OIs) Describe the most common OIs in Vietnam including: clinical presentation diagnosis national treatment recommendations

3. 3 What is an Opportunistic Infection (OI)? An infection caused by pathogens that usually do not cause disease in a host with a healthy immune system A compromised immune system presents an "opportunity" for the pathogen to infect

4. 4 What is the Relationship Between CD4 Count and OIs? The lower a person’s CD4 count is, the more vulnerable he/she is to opportunistic infections (OIs) Different infections can occur based on how weak a person’s immune system is The level of CD4 count determines the OIs for which a person is at risk

5. 5 Sample OIs per CD4 Count CD4 CountOI / Condition > 500/mm3 Candidal vaginitis Persistent generalized lymphadenopathy 200-500/mm3 Pneuomoccal pneumonia Pulmonary tuberculosis Herpes zoster Oropharyngeal candidiasis (Thrush) < 200/mm3 Pneumocystis jiroveci pneumonia Miliary/extrapulmonary TB < 100/mm3 Candida Esophagitis Penicilliosis Toxoplasmosis Cryptococcosis < 50/mm3 Mycobacterium avium complex (MAC) Disseminated cytomegalovirus (CMV)

6. 6 Key Principles of OI Diagnosis and Treatment Accurate diagnose of OIs require consideration of: Clinical features Severity of immunosuppression Results of specific lab tests Patients often have multiple OIs at the same time Drug-drug interactions are an important consideration in the management of OIs

7. 7 Clinical Presentation, Diagnosis and Treatment of Major OIs in Vietnam

8. 8 What are Common OIs in Vietnam? Oral Candidiasis (Thrush) Tuberculosis Penicilliosis Cryptococcal Meningitis PCP Cerebral Toxoplasmosis Cytomegalovirus (CMV) Retinitis Mycobacterium Avium Complex (MAC) Cryptosporidiosis Isosporiasis and Cyclosporiasis

9. 9 Oral Candidiasis (Thrush) Most patients have no symptoms Shows as white plaques on palate, gums Treatment: 1.Fluconazole 150mg/day for 7 days 2.Ketoconazole 200mg bid for 7 days White plaques on palates, removable by tongue blades

10. 10 Candida Esophagitis Patients complain of: pain in throat or chest when swallowing food getting “stuck” Treatment Flu200mg/day for 14 days Itra400 mg/day for 14 days Keto200 mg bid for 14 days

11. 11 Tuberculosis (1) TB is the most common OI in Vietnam and the most common cause of death among HIV patients Clinical symptoms of pulmonary TB include fever, cough, night sweats, weight loss, and bloody sputum Extrapulmonary TB is more common in HIV+ compared to HIV- patients

12. 12 Tuberculosis (2) Diagnosis: Clinical symptoms CXR Sputum AFB smear Bronchoscopy where available Tissue biopsy (lymph nodes) Right upper lobe infiltrate

13. 13 Pneumocystis jiroveci Pneumonia (PCP) (1) Clinical manifestations include: gradual onset of shortness of breath dry cough fever Lung sounds may be clear or have faint crackles Hypoxia is common Elevation of LDH is common but nonspecific CD4 <200 (though occasionally higher)

14. 14 Pneumocystis jiroveci Pneumonia (PCP) (2) Typical CXR bilateral diffuse infiltrations Atypical CXR normal result blebs and cysts lobar infiltrates Suggestive CXR pneumothorax

15. 15 PCP Diagnosis (1) Diagnosis can be made clinically Empiric treatment should be started if the diagnosis is suspected Definitive diagnosis is made by sputum smear and stain Fluorescent stain

16. PCP Treatment Condition, Medication Treatment regimen Trimethoprim- sulfamethoxazole (Cotrimoxazole) 15-20 mg/kg/day (of TMP) for 3 weeks For severe cases, add prednisone (for 21 days) 40 mg twice daily for 5 days, then: 40 mg daily for 5 days then: 20 mg/day for 11 days Then, chronic suppressive therapy: Cotrimoxazole 160/800 mg daily Discontinue when CD4 >200 for 6 months on ARV National Treatment Protocol

17. 17 Case Study: Duc (1) Duc, a 30 year-old HIV positive man, presents to OPC with cough of 3 weeks duration Scanty whitish sputum Low grade fever Developed shortness of breath one week ago On examination he was in respiratory distress with RR of 40/min and cyanosis What are the likely causes? What important tests would you request?

18. 18 Case Study: Duc (2) Results of tests: Sputum AFB: negative 3 times CXR: bilateral infiltrates CD4: 110/mm3

19. 19 Penicilliosis (1) Causative agent Penicillium marneffei First isolated in 1956 in Vietnam from the bamboo rat Endemic in southeast Asia and southern China First case reported in an AIDS patient was in Vietnam in 1996 Majority of cases occur in patients with CD4 cell counts < 100 Source: Hien TV et al. CID 2001;32:e78-80.

20. 20 Penicilliosis (2) Most common signs and/or symptoms include: Fever Weight loss Skin lesions Lymphadenopathy Hepatomegaly Splenomegaly Anemia Elevated AST, ALT

21. 21 Typical Skin Lesions of P. Marneffei Cutaneous papules with central necrotic umbilication. May be confused with molluscum contagiosum or disseminated cryptoccocus.

22. 22 Penicilliosis - Diagnosis P. marneffei cultures (blood or skin lesions) produce a distinct red diffusible pigment Culture Wright stain of skin lesions Direct microbiological exam

23. 23 Penicilliosis - Treatment National Treatment Protocol ConditionTreatment Regimen Severe cases Amphotericin B 0.7mg/kg/day IV for 2 weeks Then itraconazole 200mg 2x/day for next 8-10 weeks Mild to moderate cases Itraconazole 200mg 2x/day x 8 weeks Maintenance therapy Itraconazole 200 mg/day Discontinue when patient is on ART and has CD4 count > 200 cells/mm3 ≥ 6 months

24. 24 Cryptococcal Meningitis (1) Clinical manifestations: Headache, fever, nuchal rigidity, fatigue, mental disorders Course can be chronic (months) Meningeal signs may be absent in advanced AIDS cases CD4<100

25. 25 Cryptococcal Meningitis (2) Diagnosis of CM is done by examining cerebral spinal fluid (CSF) after performing a lumbar puncture Opening pressure CSF parameters (cell count, protein, glucose) Microbiology India Ink stain Cryptococcal antigen test CSF culture

26. 26 Cryptococcal Meningitis - Treatment ConditionTreatment Regimen Preferred regimen Amphotericin B 0.7mg/kg/day IV for 2 weeks Then Fluconazole 800- 900 mg/day for next 8 weeks. Mild cases or if amphotericin not available Fluconazole 800-900 mg/day for 8 weeks Maintenance therapy Fluconazole 150-200 mg/day Discontinue when patient is on ART and has CD4 count > 200 cells/mm3 ≥ 6 months *With management of elevated intracranial pressure

27. 27 Cerebral Toxoplasmosis Seen in patients with CD4<100 Clinical manifestations: Fever Headache Confusion Motor weakness Focal neurological deficit Seizures, stupor, coma

28. 28 Cerebral Toxoplasmosis – Diagnosis (1) MRI of cerebral toxoplasmosis showing 2 ring enhancing lesions – “lighting up” with intravenous contrast

29. 29 Cerebral Toxoplasmosis – Diagnosis (2) Empiric treatment with good clinical response (+/-) improvement of brain imaging Positive blood serology (IgG) to T. gondii Indicates prior infection Negative serology makes cerebral toxoplasmosis less likely Brain or tissue biopsy crescent/banana shaped tachyzoites

30. 30 Cerebral Toxoplasmosis: Treatment Treatment Type Medication Regimen Acute Treatment Cotrimoxazole: TMP 10 mg/kg/day intravenously or orally for 3-6 weeks OR: Pyrimethamine: 200 mg loading dose, then 50-75 mg once daily + Sulfadiazine: 2-4g/initial dose, then 1- 1.5 g every 6 hours for 3-6 weeks Maintenance Therapy Pyrimethamine: 25-50 mg/day + Sulfadiazine: 1g x every 6 hours OR: Cotrimoxazole 960 mg (SMX 800mg / TMP 160mg) orally once per day Discontinue when patient is on ART with CD4 count > 100 cells/mm 3 ≥ 6 months

31. 31 Case Study: Huong Huong, a 31 year-old HIV-positive woman from Hanoi, presents with weakness of left upper and lower extremities for 5 days duration Complains of fever, severe headache and vomiting for last 2 weeks Not taking any medication Examination revealed a confused woman with weakness of left extremities but no meningeal signs What is Huong’s differential diagnosis?

32. 32 Mycobacterium Avium Complex (MAC) Prevalence unknown in Vietnam 3% of cohort of AIDS patients in Hanoi Manifestations CD4 < 50 Fever Weight loss Lymphadenopathy Hepatosplenomegaly Anemia Diagnosis Blood culture Bone marrow and lymph node biopsies with culture Treatment Clarithromycin or azithromycin PLUS ethambutol

33. 33 Cytomegalovirus (CMV) Retinitis Presentation: CD4 < 50 blurred vision blind spots “floaters” blindness painless condition Treatment: Ganciclovir intravitreal* or intravenous injections ART * Ganciclovir intravitreal injections are available at the national level in both north and south Vietnam

34. 34 Cryptosporidiosis (1) Caused by infection with C. parvum generally infects small bowel mucosa Transmission ingestion of the cysts (usually in water contaminated with feces) Can affect patients at any CD4 count CD4 < 100 are at highest risk for most severe infection

35. 35 Cryptosporidiosis (2) Clinical presentation acute or subacute non-bloody, watery diarrhea nausea and/or vomiting lower abdominal cramps fever can occur Diagnosis Modified AFB stain Treatment Supportive ART to raise CD4 count

36. 36 Isosporiasis and Cyclosporiasis Transmitted by ingestion of contaminated food and water Clinical presentation chronic voluminous watery diarrhea abdominal cramps, nausea/vomiting weight loss Treatment TMP-SMX 2 DS tablets twice or three times daily for 2 – 4 weeks ART to raise CD4 counts

37. 37 Case Study A 32-year-old IDU comes to the clinic complaining of persistent diarrhea that started five months earlier You do a CD4 count and stool exam His CD4=70 His stool reveals cryptosporidium How would you classify his clinical stage? With a CD4 count of 70, what other OIs is he at risk for?

38. 38 Key Points An OI is caused by pathogens that usually do not cause disease in a healthy host Knowing a PLHIV’s CD4 count can help clinician better diagnose an OI Accurate diagnose of OIs require consideration of: Clinical features Severity of immunosuppression Results of specific lab tests

39. 39 Thank you! Questions?