Case Approach in HIV

..

Management of Opportunistic Infections

AIDS-defining illnesses (>10 years of age) reported to MOPH, Thailand,1994-1998 Tuberculosis (28.9%) Pneumocystis carinii pneumonia (PCP) (19.8%) Cryptococcosis (18.5%) Cerebral toxoplasmosis (3.1%) Disseminated Mycobacterium avium complex infection (DMAC) (0.2%) Cytomegalovirus diseases (0.6%) Salmonella septicemia (0.5%) Penicilliosis (3.0%) Histoplasmosis (0.3%)

Common Presentations of OIs in HIV-infected Patients

Fever Lymphadenopathy Respiratory symptoms Diarrhea/ other GI symptoms Cutaneous lesions Neurological symptoms Decreased vision

Fever in HIV-Infected Patients

Potential causes of fever in HIV 1. Opportunistic infections 2. AIDS-associated tumors 3. Complications of drug treatment 4. HIV infection itself

Approach to HIV-infected patients with fever

Approach to diagnosis of fever in HIV localizing findings Yes work up targeting specific organ system - sinusitis - pulmonary - hepatobiliary/GI - cytopenia - neurological - Adenopathy - skin, iv line No If CD4 <200: OI prophylaxis? CBC, differential, U/A blood culture for bacteria,mycobacteria cryptococcal antigen AST, ALT, Alk Phos CXR, stool AFB Treat as salmonellosis?

Lymphadenopathy in HIVInfected Patients

Lymphadenopathy
Any of the following present? -Fever -Weight loss -Asymmetrical node enlargement -Matted nodes -Fluctuated nodes -Tender nodes -Extranodal foci e.g., skin lesion No PGL
-CXR

-LN aspiration for AFB, Gram and Wright stains

Diagnostic?

No LN biopsy

Yes

Lymphadenopathy in HIV-infected Patients Tuberculosis NTM infections Nocardiosis Salmonellosis Fungal infection: cryptococcosis, histoplasmosis, penicilliosis Malignancy: lymphoma, Kaposis sarcoma

Pulmonary symptoms and/or pulmonary infiltrates

History

acute vs. subacute/ chronic endemic region of specific pathogen Productive vs. nonproductive cough Past pulmonary infection and adherence to OI prophylaxis IVDU S. aureus pneumonia

Physical signs General: wasting, oral thrush Lungs Cutaneous/mucocutaneous lesions Peripheral adenopathy Neurological signs Hepatosplenomegaly

CD4 cell count range for selected HIV-related and non-HIV-related pulmonary diseases Any CD4 - bacterial pneumonia - TB - NHL - bronchogenic CA - pulm. embolism CD4 < 200 - PCP - Cryptococcal pneumonia - bacterial pneumonia - diss. or extrapulm. TB CD4 < 500 - Bacterial pneumonia (recurrent) - TB and NTM

CD4 cell count range for selected HIV-related and non-HIV-related pulmonary diseases (cont d)

CD4 < 100 - pulmonary KS - bacterial pneumonia - toxoplasma pneumonitis

CD4 < 50 - diss. histoplasmosis - CMV pneumonitis - diss. MAC - diss. TB

HIV-infected pt. with pulmonary symptoms and/or abnormal CXR Induced sputum nondiagnostic Diagnostic Bronchoscopy, BAL + TBB nondiagnostic

Start treatment Observation + empiric treatment

VATs/open lung biopsy

Investigations: Chest x-ray Sputum : gram stain, acid-fast stain, modified stain, geimsa stain, silver stain, IFA Bronchoscopy - BAL or BW, TBB Extrapulmonary samples blood culture: bacteria, mycobacteria, fungi serum cryptococcal antigen lymph node aspiration/biopsy bone marrow aspiration/biopsy liver biopsy skin scraping, biopsy CSF study

Differential diagnosis of pulmonary complications based on radiographic findings Diffuse reticulonodular infiltrates - PCP - TB - Histoplasmosis - Penicilliosis - CMV - H. influenzae - Nonspecific interstitial pneumonitis - Viral pneumonia - Toxoplasmosis
Modified from: Bartlett JG, Gallant JE. 2000-2001 Medical Management of HIV Infection.

PCP

Cryptococcosis

Consolidation - Pyogenic bacteria - TB - Nocardiosis - M. kansasii - Cryptococcosis - Rhodococcosis - KS

Rhodococcosis

PCP

Nodules/mass - TB - Cryptococcosis - KS - Lymphoma - Septic emboli - Lung cancer

Nocardia

Cavitary disease
- Bacteria (P. aeruginosa, S. pneumoniae, S. aureus, K. pneumoniae) - TB - Nocardia - M. kansasii, NTM - Cryptococcosis - Histoplasmosis - Aspergillosis - Rhodococcosis - Anaerobic bacteria - PCP (rare) - M. avium complex (rare) - Lymphoma, malignancies

Pleural effusion
- Bacteria (S. aureus, S. pneumoniae) - TB - KS (bloody) - Cryptococcosis - Rhodococcosis (rare) - Septic emboli - Aspergillosis - Histoplasmosis (rare) - Lymphoma (rare) - M. avium complex (rare) - PCP (rare)

- Other noninfectious causes

Hilar adenopathy - TB - Cryptococcosis - M. avium complex - Histoplasmosis - KS - Lymphoma

Normal - PCP - Endobronchial TB

Case 1
A 30 y/o HIV-infected male presented with productive cough, progressive weight loss, fatigue, and fever for 1 week. Exam: T 38.3oC, wasting, oral thrush, OHL, no HSM. O2 saturation at room air = 96%

Case 1
CBC: Hct 27.8%, WBC 4,900/mm3, N99%, plt 115,000 TB 1.6, AST 123, ALT 34, alk phos 257 (39-117), LDH 779 (225-450)

Case 1

What are the differential diagnosis?

Case 1
Differential diagnosis Bacterial pneumonia Tuberculosis Fungal pneumonitis Nocardiosis NTM

Case 1
What are the appropriate work up?

Case 1
Sputum for gram stain, modified acidfast stain, acid-fast stain Sputum culture for bacteria, mycobacteria and fungi CD4 cell count (serum cryptococcal antigen)

Case 1
H/C for bacteria : no growth Sputum for AFB + AFB rare Serum cryptococcal antigen: negative What is the provisional diagnosis? What treatment would you start while awaiting culture result?

Case 1
Empirically treated as Tuberculosis with INH, RIF, PZA and EMB. 2 weeks later: Rt. pneumothorax , ICD, pleurodesis

Case 1
Sputum culture: M. tuberculosis H/C for mycobacteria: M. tuberculosis

Case 2
32 y/o newly diagnosed HIV-infected male 2 weeks history of fever, productive cough, weight loss, SOB Exam: T 39.2oC, RR 24/min, BP 110/80 mmHg, oral thrush Lungs: CTA multiple small cervical nodes O2 saturation at room air = 97%

Case 2
CBC: Hct 25%, WBC 4,100/mm3, plt 125,000 CD4 = 39/mm3 LDH 570 Chest x-ray: RUL infiltrates

Case 2
What are your differential diagnosis?

Case 2
Tuberculosis NTM pneumonitis Nocardiosis Rhodococcosis Cryptococcosis

Case 2
What are the appropriate work up?

Case 2
Sputum exam. for gram stain, modified acid-fast and acid-fast stains were negative. Sputum cultures for bacteria, mycobacteria, fungus are pending What would you do?

Case 2
Bronchoscopy: BAL positive for gram-positive branching filamentous bacilli and modified acid-fast positive branching bacilli Acid-fast stain was negative.

Case 2
What is your provisional diagnosis? What would you recommend for empiric treatment?

Case 2
Co-trimoxazole was given. Patient gradually improved. BAL culture grew Nocardia asteroides; no mycobacteria isolated.

Case 3
26 y/o HIV-infected male 2 weeks history of fever, productive cough, chest pain, fatigue and anorexia. Exam: T 39oC, RR 24/min OHL, pruritic papular eruption Lungs CTA small cervical nodes no HSM O2 saturation at room air = 98%

Case 3
CBC: Hct 31%, WBC 3,000/mm3, N 50%, plt 110,000 CD4 = 11/mm3 LDH 452

Case 3
What are the differential diagnosis? What are the appropriate investigation?

Case 3
Differentail diagnosis Nocardiosis Rhodococcosis Tuberculosis NTM Fungal infection: Aspergillosis, Cryptococcosis Lymphoma

Case 3
Sputum for gram stain, modified acidfast and acid-fast stains Sputum cultures for bacteria, mycobacteria and fungi

Case 3
What is the diagnosis?

Case 3
What are the treatment of choice?

Case 3
Sputum culture grew Rhodococcus equi. The patient was treated with vancomycin + rifampicin. Fever subsided with clinical improvement after 2 weeks, azithromycin + rifampicin were given as out-patient treatment.

Rhodococcosis (1)
Gram positive aerobic pleomorphic coccobacilli In AIDS, average CD4 50/mm3 Pneumonia is most common form, caused by inhalation

Rhodococcosis (2)
Clinical manifestation: Subacute onset Pneumonia Extrapulmonary not uncommon subcutaneous,renal, pelvic, brain abscess, osteomyelitis, mycetoma, endophthalmitis In immunocompromised, relapse common ~ 80% if no maintenance treatment

Rhodococcosis (3)
Diagnosis: sputum c/s and blood c/s positive > 50% modified acid fast positive CXR - consolidation , cavity ( >75% with air fluid level ), mass lesion, pleural effusion ( 18-35% ), may precede with interstitial infiltrate

Rhodococcosis (4)
Optimal regimen and duration is unknown Initial therapy - at least 2 drugs for 2-3 months e.g., macrolide + rifampicin or vancomycin + rifampicin or imipenem + rifampicin Maintenance therapy - 2 susceptible drugs life-long

Case 4
26 y/o HIV-infected female On TMP/SMX DS 1 tab OD 2 weeks history of fever, headache, productive cough, myalgia, 2-3 small volume watery diarrhea per day Exam: T 40.2oC, RR 20/min,BP 120/80 mmHg, oral thrush, wasting. Otherwise unremarkable CBC: Hct 25.2%, MCV 72.9, WBC 4,600 N 88%, plt 383,000, LDH 818 U/L (normal 225-450)

Case 4
Treatment: ciprofloxacin 500 mg PO BID H/C for bacteria, mycobacteria serum cryptococcal Ag stool for parasites and modified AFB stain Chest x-ray: RUL cavitating lesion with adjacent focal alveolitis and RLL infiltrates.

Case 4
What are the differential diagnosis?

Case 4
Differential etiologies of pulmonary cavity - Tuberculosis - NTM infection - Nocardiosis - Fungal pneumonia - Rhodococosis - lymphoma

Case 4
Stool: RBC 1-10/HPF, WBC 1-10/HPF, no parasite, mod. acid-fast stain negative Sputum negative for AFB x 2 Sputum for Gram stain: numerous Gram + cocci, few budding yeasts with capsules, bacterial culture - moderate growth of yeasts

Case 4
Bronchoscopy : nondiagnostic gross finding, BAL and TBB of LLL

Case 4
Serum cryptococcal Ag + 1:256 L.P. CSF open pressure 8 cmH2O WBC 1, RBC 12,650, protein 67 mg/dL, glucose 42 mg/dL, india ink negative, cryptococcal Ag negative

Case 4
BAL: C. neofromans TBB: acute and chronic inflammation with yeasts suggestive of Cryptococcus H/C for bacteria: C. neoformans H/C for mycobacteria: C. neoformans H/C for fungus: C. neoformans

Case 4
Patient improved after amphotericin B treatment.

Case 4
Final diagnosis: 1. Disseminated cryptococcosis (blood, lung) 2. AIDS

Case 5
36 y/o male with AIDS AZT, ddI and IDV experienced Loss to follow-up for 2 years without taking any medication 2 weeks history of fever, gradually progressive SOB Presented with sudden onset of severe SOB Exam: T 38oC, P 110/min, RR 32/min dyspnea, decreased breath sounds both lungs

Case 5
Chest x-ray: bilateral pneumothoraces with diffuse infiltrations of residual lungs.

Case 5
What is the most likely diagnosis?

Case 5
What is the appropriate management?

Case 5
Lt. ICD was inserted. Transthoracic needle aspiration of Rt. Pneumothorax was performed. Oxygen therapy Patient was treated with co-trimoxazole and corticosteroids for presumptive PCP with prompt response.

PCP (1)
CD4 <200/mm3 subacute respiratory complaints progressing over weeks to months fever, dyspnea, nonproductive cough LDH, sensitive but nonspecific

PCP (2)
Chest x-ray: bilateral interstitial or nodulointerstitial infiltrates normal CXR ~ 10% atypical CXR apical infiltrates and pneumothoraces in patients receiving prophylactic aerosol pentamidine.

PCP (3)
Diagnosis induced sputum: Giemsa, silver, direct or indirect immunofluorescent stains Sensitivity varies but approach 90% Bronchoscopy: - BAL sensitivity 79-98% - TBB sensitivity 94-100%

PCP (4)
Treatment Drug of choice : - TMP/S (15-20 mg/kg/d of TMP in 3-4 divided doses po or iv) Alternative drugs : - clindamycin 600 mg iv q 8 h or 300-450 mg po q 6 h + primaquine 30 mg base po/d - pentamidine 4 mg/kg/d iv - TMP + dapsone 100 mg/d po - Atovaquone Duration of treatment : 21 days

PCP (5)
If PaO2 <70 mm Hg, or A-a gradient >35, add corticosteroids prednisolone 40 mg b.i.d. x 5 d, then 40 mg q.d. x 5 d, then 20 mg q.d. x 11 d

PCP (6)
Primary prophylaxis : Indications : CD4 < 200 history of OC CD4 <14% history of other AIDS-defining illness First choice : TMP/S 1 DS or 1 SS q.d. Alternatives : dapsone 100 mg q.d. TMP/S 1 DS t.i.w. dapsone + pyrimethamine + folinic acid aerosolized pentamidine (atovaquone)

PCP (7)
Secondary prophylaxis : Indication : history of PCP Preventive regimens : as in primary prophylaxis Discontinuation of secondary prophylaxis : increase in CD4 to >200/mm3 for > 3 months in response to HAART Restarting secondary prophylaxis : CD4 decreases to <200/mm3 PCP recurred at CD4 >200/mm3

Case 6
32 y/o homosexual HIV-infected male with history of PCP, CD4 = 75/mm3 Medications: TMP/SMX DS 1 tab OD, fluconazole 400 mg/wk Developed violaceous nodules and plaques on face, extremities, back and ears that progressively increased in number and size over the past 3 months. He has had dry cough, increasing SOB for 2 weeks

Case 6
Exam: T 37.5oC, RR 28/min, skin lesions as stated violaceous lesion on the palate Lungs crackles both lungs O2 saturation at room air = 89% Chest x-ray

Case 6
What is the most likely diagnosis?

Case 6
How to make the diagnosis?

Meningitis in HIV
Common etiologies: Cryptococcus neoformans M. tuberculosis Cytomegalovirus Bacteria: S. pneumoniae

Cryptococcal meningitis (1)

Subacute meningoencephalitis: headache, nausea, irritability, decline in cognitive function to frank obtundation fever, neurologic deficits, papilledema meningismus ~ 40% pulmonary, cutaneous (disseminated cryptococcosis)

Cryptococcal meningitis (2)

Complications: hydrocephalus, seizures, neuro. deficits, cerebellar dysfunction, and dementia Diagnosis: - CSF : cryptococcal antigen, India ink stain, culture - serum cryptococcal antigen - sputum, skin, BM, blood culture

Cryptococcal meningitis (3)

Treatment for cryptococcal meningitis in AIDS Induction therapy amphotericin B 0.7 mg/kg/d iv x 10-14 d (+ flucytosine 100 mg/kg/d po) Consolidation therapy fluconazole or itraconazole 400 mg/d x 10 wks Maintenance therapy (secondary prophylaxis) fluconazole 200 mg po q.d. or ampho B 0.6-1 mg/kg iv q.w.-t.i.w. or itraconazole 200 mg po q.d.

Cryptococcal meningitis (4)

MOPH National Guidelines, 7th ed. 1o prophylaxis for CM is indicated when CD4 <100/mm3 fluconazole 400 mg q wk

Cryptococcal meningitis (5)

Adjunctive therapy for management of elevated CSF pressure in CM
large-volume CSF drainage neurosurgical shunting acetazolamide ? corticosteroids ?

Cerebral toxoplasmosis (1)

CD4 <100/mm3 Fever, altered mental status, headache, seizures, or neurological deficit Serum Toxoplasma IgG + (84%)* CT or MRI: multiple ring-enhancing lesions
* Porter & Sande. N Eng J Med 1992;23:1643-8.

Cerebral toxoplasmosis (2)

Treatment Drugs of choice: sulfadiazine 4-6 g/d + pyrimethamine 200 mg loading, followed by 50-100 mg/d + folinic acid 10 mg/d Alternatives: clindamycin + pyrimethamine + folinic acid dapsone + pyrimethamine + folinic acid azithromycin + pyrimethamine + folinic clarithromycin + pyrimethamine + folinic acid

Cerebral toxoplasmosis (3)

Prevention of Toxoplasmosis In toxoplasma seronegative patients - not to eat raw or undercooked meat - wash hands after contact with raw meat, gardening or soil contact - wash fruits and vegetables well before eating them raw - avoid cat contact - Cats should be fed only canned or dried commercial food or well-cooked table food.

Cerebral toxoplasmosis (4)

Primary prophylaxis : CD4 < 100/mm3 and toxoplasma IgG + Drug of choice: TMP/S 1 DS po q.d. Alternatives: TMP/S 1 SS po q.d. dapsone + pyrimethamine + folinic acid atovaquone + pyrimethamine + folinic acid

Cerebral toxoplasmosis (5)

Prevention of recurrence (2o prophylaxis) Drugs of choice: sulfadiazine 0.5-1g po q.i.d. + pyrimethamine 25-50 mg po q.d. + folinic acid 10 mg/d Alternatives: clindamycin + pyrimethamine + folinic acid atovaquone + pyrimethamine + folinic acid

Case 7
34 y/o M, newly diagnosed HIV Headache, Lt-sided weakness and seizure T 38oC, mild confusion, Lt. hemiparesis CD4 = 15/mm3 CT brain

Case 7
What are the differential diagnosis? What are the initial appropriate work up and management?

Case 7
Serum toxoplasma IgG negative Sulfadoxine, pyrimethamine, folinic acid, phenytoin and prednisolone initiated without response

Case 8
29 y/o HIV-infected female, not on medication Headache, vomiting, seizure, Exam: obtunded, Lt. hemiparesis CT brain

Case 8
What are the differential diagnosis? What are the appropriate initial work up and management?

Case 8
Serum toxoplasma IgG negative Sulfadoxine, pyrimethamine, folinic acid, phenytoin and prednisolone initiated without response

Criteria for initiation and discontinuation of OI prophylaxis

1o prophylaxis PCP Toxo. Cryptococ. DMAC CD4 <200 or OC CD4 <100, Toxo. IgG+ CD4 <100 (MOPH) CD4 <50 CD4 > 100, > 3 mo. CMV Stop 1o prophylaxis CD4>200, > 3 mo. CD4>200, > 3 mo. CD4 >200, > 6 mo., asymptomatic CD4>100-200, > 6 mo. CD4 >100, > 6 mo., > 12 mo. of MAC Rx CD4 >100-150, asymptomatic Stop 2o prophylaxis CD4>200, > 3 mo.

Cutaneous manifestations of systemic infection

P. marneffei : small oval, round, sausage shaped yeast with central clear septum (binary fission) (3-8 micron)

Courtesy by Supparatpinyo K.

H. capsulatum : small budding yeasts intracellular and extracellular

Tubercolosis (1)
may present at any stage of HIV infection In early HIV disease, pulmonary TB is similar to that found in HIV-negative people. In advanced immunodeficiency, TB is often disseminated and multibacillary in nature. Active TB increases HIV replication and viral load. Sputum culture and susceptibility tests are crucial.

Tuberculosis (2)
Treatment standard regimens as for TB in non-HIV. 2HRZE/4HR for drug sensitive TB outside CNS At least 182 doses of HR and 56 doses of ZE 2 HRZE/10 HR for drug sensitive CNS TB .

BHIVA Guidelines for TB/HIV infection Feb 2005

Tuberculosis (3)
Treatment (continued) 9-month therapy recommended if symptomatic at 2 mo. or positive culture after 2 months of therapy* or cavitary disease or TB of bone and joint Consider DOT to improve compliance.

* CDC, NIH, IDSA Recommendations. MMWR 2004, 53:37

ATS,

CDC, IDSA joint statement: Treatment of Tuberculosis Oct 2002

Tuberculosis (4)
Special Treatment Situations HIV/AIDS*
Treatment for HIV-positive patients same as for HIV-negative patients, except - Once-weekly INH-rifapentine in continuation phase is contraindicated in HIV-positive patients - Twice-weekly INH-RIF or INH-rifabutin should not be used in patients with CD4 <100/mm3 Every effort should be made to use a rifamycinbased regimen for the entire course of therapy
*ATS/CDC/IDSA: treatment of tuberculosis. Am J Respir Crit Care Med 2003;167:603-62.

Tuberculosis (5)
TB treatment in patients with liver disease
If AST >3X ULN before treatment initiation - Standard therapy with frequent monitoring or - Rifamycin and EMB and PZA for 6 mo. or - INH and rifamycin and EMB for 2 mo, then INH and rifamycin for 7 months (BII) For patients with severe liver disease - Rifamycin and EMB for 12 months (preferably with another agent such as fluoroquinolone for first 2 months)
MMWR 2004;53

Tuberculosis (6)
Hepatotoxicity while on anti-TB drugs
AST or ALT > 3X ULN with symptoms AST or ALT > 5X ULN without symptoms All potentially hepatotoxic drugs should be stopped immediately Once AST drops to <2X ULN and symptoms significantly improved, reintroduced first line medications
*BHIVA Guidelines for TB/HIV infection Feb 2005

Tuberculosis (7)
HAART and Rifampicin NNRTIs and PIs metabolized by CYP450 Rifampicin induced CYP450 ARVs that may be used with rifampicin
2 NRTIs + efavirenz (EFV) dose? (nevirapine?) 2 NRTIs + ritonavir (RTV) (600 mg bid) 2 NRTIs + saquinavir (SQV) (400 mg bid) + RTV (400 mg bid)???? Increased hepatotoxicity 2 NRTIs + lopinavir (400 mg bid) + RTV (400 mg bid) 3 NRTIs MMWR 2004;49

Tuberculosis (8)
EFV: 800 mg/d for patients >50 kg* 600 mg/d for patients <50 kg* NVP: controversial BHIVA (Feb 2005) - should not be used* CDC (2004) - should only be used when no other options are available with close monitoring WHO (2003) may be used in place of EFV in absence of other options

*BHIVA Guidelines for TB/HIV infection Feb 2005

Tuberculosis (9)
Protease inhibitors (PIs) BHIVA (Feb 2005) unboosted PI should not be used. TDM of NNRTI and PI when regimens are complex WHO (2003) SQV/rtv 1000/100 mg bid or 1600/200 mg qd as alternative to EFV

Tuberculosis (10)
When to start HAART in HIV/TB co-infection Optimal time for initiating ART during TB treatment is unknown. Decision should be individualized (patients initial response to TB therapy, occurrence of side effects, and acceptance of multidrug ART) Most would wait at least 4-8 weeks (BIII)
MMWR 2004;53

Tuberculosis (11)
When to start HAART in HIV/TB co-infection* CD4 <100 100-200 >200
regular

When to treat with HAART as soon as possible-dependent on physician assessment after 2 months of TB treatment after completing 6 months TB treatment

6-8 weekly CD4 count monitoring; if CD4 count falls patients may need to start HAART
*BHIVA Guidelines for TB/HIV infection Feb 2005

Tuberculosis (12)
Paradoxical (Immune reconstitution) Reaction
Temporary exacerbation of symptoms, signs or radiographic manifestations of TB disease after beginning anti-TB treatment 11 to 36% (after ART) vs. 7% (no ART) Weeks-months (1-3 months), median 15 days Inflammation from immune response to mycobacterial antigen High fever, enlargement and inflammation of pre-existing lesions, or development of new foci, expanding CNS mass lesion, worsening pulmonary infiltrates and increasing pleural effusion.
BHIVA Guidelines for TB/HIV infection Feb 2005 CDC, NIH, IDSA Recommendations. MMWR 2004;53 Int J Tuberc Lung Dis 2001;5:370-5.

Tuberculosis (13)
Paradoxical Reaction Differential diagnosis Treatment failure Anti-TB side effects Other OIs or malignancy Self-limited, generally 10-40 days Anti-TB and ART need not be changed/stopped Prednisolone for severe reaction: high fever, airway obstruction, serosal fluid collections, expanding CNS lesions and sepsis syndrome
BHIVA Guidelines for TB/HIV infection Feb 2005 CDC, NIH, IDSA Recommendations. MMWR 2004;53 Int J Tuberc Lung Dis 2001;5:370-5.

WHO recommendation of ART for TB and HIV co-infections

CD4 <200/mm3

Recommend ART as soon as TB treatment is tolerated (between 2 wks - 2 mo.) Consider ART after initiation phase of TB treatment (unless severely compromised) Defer ART

CD4 200-350/mm3

CD4 >350/mm3

Scaling up antiretroviral therapy in resource-limited settings : Guidelines for a public health approach. DRAFT VERSION FOR PUBLIC CONSULTATION. WHO October 2003

Initiation of ART in nave patients with acute OI

Concern of immediate initiation of ART concurrent with diagnosis of OI Drug toxicities Drug interactions Adherence IRIS fever, worsening of clinical manifestations of OI or new manifestations weeks after initiation of ART

Initiation of ART in nave patients with acute OI

ART should be started as soon as possible (AIII) Cryptosporidiosis Microsporidiosis PML KS

Management of acute OI in setting of ART

OIs that occur shortly after initiating ART (within 12 weeks) subclinical infections unmasked by early immune reconstitution OIs occurring > 12 weeks after initiation of ART specific therapy is indicated if organisms identified by stain and culture OIs in patients with virological and immunological failure

When to initiate ART in setting of OI

For TB, MAC, PCP and CM, await response to OI therapy before initiating ART (CIII) When OI occurs within 12 weeks of starting ART, treatment of OI should be started and ART should be continued (AIII) Late OI (despite complete virologic suppression), therapy for OI should be initiated, ART should be continued Modification of ART if CD4 cell response is suboptimal (CIII) When OI occurs in setting of virological failure, OI therapy should be started, ARV resistance testing and modified ART regimen (AI)

Disseminated M. avium complex infection (1)

CD4 <50/mm3 Prolonged fever, wasting, anemia, hepatomegaly, splenomegaly, intraabdominal lymphadenopathy, chronic diarrhea Pulmonary disease is uncommon Diagnosis: BACTEC culture for Mycobacteria (blood, bone marrow) AFB + from clinical specimens need to be differentiated MAC from M. tuberculosis and other NTM by culture.

Disseminated M. avium complex infection (2) Treatment clarithromycin 500 mg po B.I.D. (or azithromycin 500 mg O.D.) + ethambutol 15 mg/kg/d + either rifabutin 450-600 mg/d or ciprofloxacin 500 mg b.i.d.

Disseminated M. avium complex infection (3) Primary prophylaxis CD4 <50 cells/mm3 DMAC should be ruled out by clinical assessment + blood culture for MAC. azithromycin 1,000-1,250 mg po q week or clarithromycin 500 mg po b.i.d.

Disseminated M. avium complex infection (4) Prevention of recurrence Patients with DMAC should receive lifelong therapy (secondary prophylaxis or maintenance therapy), unless immune reconstitution occurs following HAART. clarithromycin (or azithromycin) + ethambutol + rifabutin

CMV Diseases (1)

Clinical spectrum of CMV diseases retina (CMV retinitis) brain (CMV encephalitis) spinal cord and nerve roots(CMV polyradiculopathy) lungs GI tract - oral/tongue ulcers - esophagitis - gastritis - colitis biliary tract (cholangitis) adrenal glands

CMV diseases (2)

CMV encephalitis cognitive disturbances. headache, seizures, and ambulation difficulties. frequently associated with radiculopathy. CSF: high protein level and pleocytosis

CMV diseases (3)

Diagnosis of CMV Disease of the Brain + CMV culture from CSF. + CMV by PCR of the CSF. Histology: intranuclear and/or intracytoplasmic inclusion bodies, confirmed by immunohistochemistry.

CMV diseases (4)

CMV pneumonitis frequently coexisted with other opportunistic pulmonary pathogens. CMV can be isolated from pulmonary secretions without causing disease. Clinical presentations: nonspecific fever 100%, shortness of breath 71%, cough 76% and Pao2 <75 mm Hg 88% Histopathology: focal/mild interstitial pneumonitis to severe diffuse alveolar damage with necrosis.

CMV esophageal ulcer

30 Aug 2004

15 Sep 2004

CMV diseases (5)

CMV enterocolitis Colitis - most common Cecum and ileocecal valve usually involved earliest in the disease. Vasculitis, focal or multifocal ulcerations that become progressively diffuse. Colonic perforation, toxic megacolon or progressive wasting with refractory diarrhea in untreated cases.

CMV Diseases (6)

Treatment Systemic therapy Induction therapy: ganciclovir iv 14-21 days foscarnet iv 14-21 days cidofovir iv q wk x 2 wk valganciclovir po Maintenance therapy: ganciclovir iv or po foscarnet iv cidofovir q 2 weeks valganciclovir

CMV diseases (7)

Local therapy for CMV retinitis ganciclovir intraocular implant (+ oral ganciclovir) fomivirsen intravitreal injection (foscarnet intravitreal injection) (ganciclovir intravitreal injection)

CMV diseases (8)

Prevention of exposure In patients with negative CMV IgG - use only CMV IgG-negative or leucocyte-reduced cellular blood products - use condom during sexual contact

CMV diseases (9)

Prevention of disease not generally recommended. Prevention of recurrence Following induction therapy, secondary prophylaxis (chronic maintenance therapy) is recommended for life, unless there is immune reconstitution as a consequence of HAART.

CMV Diseases (10)

HAART should be started in patients with acute CMV retinitis, GI disease or pneumonitis (BIII) Brief delay in initiation of HAART in patients with CMV neurologic disease (CIII)

CDC, NIH, IDSA Recommendations. MMWR 2004;53

Penicilliosis (1)
Penicillium marneffei Fever(93%), cough (49%), anemia (78%), skin lesions (71%), lymphadenopathy (58%), hepatomegaly (51%), splenomegaly (16%).* Diagnosis: round, oval, sausage -shaped yeasts with binary fission from staining of clinical specimens, culture. Relapse rate after successful treatment about 50% without secondary prophylaxis.
*Supparatpinyo K et al. Lancet 1994;344:110-13.

Penicilliosis (2)
Initial treatment for disseminated Penicilliosis* Amphotericin B 0.6 mg/kg/d iv x 2 weeks followed by itraconazole 200 mg B.I.D. po immediately after meal x 10 weeks. Prevention of recurrence (2o prophylaxis)** Itraconazole 200 mg O.D. po for life
***Absorption of Itraconazole is impaired by H2 blockers, omeprazole, antacid
or sucralfate and should not be given concurrently with terfenadine, cisapride or astemizole. Decreased itraconazole levels with administration of rifampicin, phenobarbital, carbamazepine, phenytoin and INH.
* Sirisanthana T et al.Clin InfectDis 1998;26:1107-10 **Supparatpinyo K : N Engl J Med 1998;339:1739-43

Penicilliosis (3)
Primary prophylaxis may be offered to HIV-infected patients with CD4 <100 cells/mm3 in endemic areas with high incidence.* Itraconazole 200 mg po q.d.
* National Guidelines for the Clinical Management of HIV Infection in Children and Adult. MOPH. 7th edition.

Histoplasmosis (1)
Histoplasma capsulatum 90% of cases have CD4 < 200/mm3. Fever, weight loss, cough and dyspnea, hepatosplenomegaly and lymphadenopathy. Subacute presentation over 1-3 months is characteristic but may be rapidly fatal.

Histoplasmosis (2)
CNS histoplasmosis - lymphocytic meningitis, focal brain lesions, or diffuse encephalitis GI: diarrhea, abdominal pain, intestinal obstruction or perforation, bleeding, or peritonitis. Skin: papules, pustules, folliculitis, plaques and ulcerations, nodules.

Histoplasmosis (3)
Diagnosis Staining of skin scraping reveal yeast cells ~ 3 m in diameter, with occasional buds. antigen detection: urine, serum culture: blood, bone marrow, respiratory secretions, or localized lesions.

Histoplasmosis (4)
Treatment the same as treatment of Penicilliosis Prevention of recurrence (secondary prophylaxis) Itraconazole 200 mg po b.i.d. alternative: amphotericin B 1 mg/kg iv q.w.

Histoplasmosis (5)
Primary prophylaxis CD4 <100/mm3, endemic geographic area Itraconazole 200 mg po q.d. Discontinuation of secondary prophylaxis no sufficient data to make recommendation at present

Case 9
28 y/o male, history of PCP, CM; on TMP/SMX and fluconazole 11/02: CD4 = 1/mm3, VL 424,946 copies/mL GPO-VIR started. 2/03: Fever x 4days, fatigue, cough with whitish phlegm T 39.4oC, BW 51 Kg. Chest x-ray: Lt. hilar adenopathy

Case 9
HB 9.6, WBC 3,100 N 56%, Platelet 423,000 SGOT 86, SGPT 80, Alk phos 437, GGT 916 HIV RNA < 50, CD4 = 36 What would you do?

Case 9
Sputum smear positive for AFB 1/3 Blood culture for Mycobacteria pending

Case 9
Fever subsided without specific antimicrobial therapy 4/03: nausea and vomiting for 3 weeks, BW 46 Kg. T 38.3oC, liver 1 FB HB 9.3, WBC 5,000 Platelet 382,000 SGOT 29, SGPT 29 UGI endoscopy: mild gastritis U/S abdomen: unremarkable Chest x-ray: remarkably enlarged Lt. hilum

Case 9
Sputum from 02/03: growth for AFB, creamy smooth colonies What treatment would you recommend?

Case 9
04/03: Chest consult - start HRZE ID - add azithromycin 05/03: Persistent fever, cough T 38.5oC, BW 49 Kg H/C : no growth for Mycobacteria 06/03: Chest x-ray new LUL and LLL infiltration, decreased Lt. hilar adenopathy : remained on HRZE+ azithromycin and GPO-VIR 07/03: d/c PZA, BW 54 Kg

Case 9
11/03: CD4 = 45, HIV RNA <50 01/04: Chest x-ray resolved infiltration and Lt. hilar adenopathy 03/04: doing well, BW 64 Kg. d/c HRE and azithromycin.

Chronic Diarrhea
Evaluation Stool fresh exam: WBC, ova & parasites Stool culture Stool stain - AFB, mod AFB Barium enema, Long GI Sigmoidoscopy, colonoscopy

Cryptosporidiosis (1)
Cryptosporidium parvum water-borne parasite As few as 120 organisms cause disease. Disease is not self limited if CD4 < 200/mm3 Clinical syndrome: severe watery diarrhea up to 20 L/d acalculous cholycystitis

Cryptosporidiosis (2)
Diagnosis: modified AFB stain endoscopy & biopsy Treatment: No effective treatment but remission may occur after HAART paromomycin, azithromycin, nitazoxanide

Microsporidiosis (1)
No known human or animal reservoir Few documented cases in non HIV patients Clinical syndrome: chronic small bowel diarrhea with malabsorption mean CD4 count 36/mm3

Microsporidiosis (2)
Four species infect humans: 2 infect intestinal cells Enterocytozoon bieneusi : more common, less responsive to therapy Encephalitozoon(Septata) intestinalis : respond to therapy with albendazole

Isosporiasis
Isospora belli large size 25 m Ingest oocyst in food and water Clinical: profuse watery diarrhea, abdominal cramping Treatment: Bactrim 2 X 4 po 10 days, then 2X2

Thank you for your attention!