AIDS and related syndrome

Clinical manifestation and staging of HIV infection

Acute HIV infection or primary HIV infection

Asymptomatic stage or clinical latency

Early symptomatic stage or AIDS-related complex (ARC)

Advanced HIV disease or AIDS

CD4 levels and common OIs

CD4 levels and common OIs

00

100100

200200

300300

400400

500500

600600

700700

800800

900900

10001000

0 1 2 3 4 5 1 2 3 4 5 6 7 8 9 10 110 1 2 3 4 5 1 2 3 4 5 6 7 8 9 10 11

CD

4+ c

ell

Co

un

tC

D4+

cel

l C

ou

nt

AsymptomaticAsymptomaticHZVHZV

OHLOHL

OCOCPPEPPE PCPPCP

CMCMCMV, MACCMV, MAC

TBTB

TBTB

MonthsMonths Years After HIV InfectionYears After HIV Infection

Natural Course of HIV Infection and Common Complications

Acute HIVAcute HIVinfectioninfection syndromesyndrome

Relative level of Plasma HIV-RNA

CD4+ T cells

VL

Advanced HIV disease or AIDS CD4+ T cell < 200 cells/mm3

Common AIDS-defining illness in HIV – infected Thai adults

– Candidiasis

– Cryptococcosis

– Penicillosis marneffei

– Histoplasmosis

– Cytomegalovirus

– Mycobacterium avium complex

– Toxoplasmosis

Candidiasis

Candida infection in AIDS is almost exclusively mucosal

Oropharyngeal candidiasis occurs in 74% of HIV-infected patients

1/3 is recurrent and more severe as immunodeficiency advances

Esophageal involvement is reported in 20 to 40% of all AIDS patients

Clinical features of oral candidiasis

Most patients are symptomatic and may complain of some oral discomfort

4 forms of oral lesions: pseudomembranous, erythematous (or atrophic), hypertrophic, and angular cheilitis

Hypertrophic type

Erythematous (atrophic) type

Pseudomembranous (thrush) type

Clinical features of vaginal candidiasis

Most patients present with vaginal itching, burning or pain and vaginal discharge

Examination of the vaginal cavity reveals thrush, identical to that seen in the oropharynx

Clinical features of esophageal candidiasis

Typical symptom: dysphagia or odynophagia

Esophageal lesions: pseudomembranes, erosions, and ulcers

Combination of oral candidiasis and esophageal symptoms is both specific and sensitive in predicting esophageal involvement

Clinical features of esophageal candidiasis

Patients who present in this manner can be treated empirically with antifungal therapy

Endoscopy is reserved in those patients who fail to respond or to evaluate for the presence of other diagnoses: HSV or CMV esophagitis, idiopathic ulceration

Diagnosis of candidiasis

Fungal cultures are rarely required for diagnosis and can cause confusion, since many patients are colonized with Candida

Scraping of a lesion will show characteristic spherical budding yeasts and pseudohyphae (KOH preparation or gram stain)

Diagnosis of candidiasis

Therapeutic options for oral candidiasis

Treatment of vulvovaginal candidiasis

Initial episodes are managed readily with topical therapy (clotrimazole, miconazole, or butoconazole)

Systemic therapy is rarely needed for uncomplicated cases

Fluconazole single dose of 150 mg orally is a popular alternative

• Drug(s) of first choice: Fluconazole 200 up to 400 mg/d x 2-3 wk

• Alternatives: Ketoconazole 200-400 mg bid x 2-3 wk or Itraconazole 100-200 mg bid or Amphotericin B 0.3-0.5 mg/kg/d IV +/- 5-FC 100 mg/kg/d x 5-7 days

Candida esophagitis

Treatment of acute infection

• Drug(s) of first choice: Fluconazole 100-200 mg/d

• Alternatives: Ketoconazole 200 mg/d or Itraconazole 200 mg/d or Nystatin or clotrimazole

Suppressive therapy

Cryptococcosis : Cryptococcal meningitis Virtually all HIV-associated infection

is caused by C. neoformans var. neoformans (serotypes A and D)

Most cases are seen in patients with CD4 <50 cells/mm3

acute primary infection or reactivation of previously dormant disease

Clinical features of cryptococcosis

Diagnosis of cryptococcosis

Wright’s stain

Acid-fast stain

Diagnosis of cryptococcosis

CSF: mildly elevated protein, normal or slightly low glucose, a few lymphocytes, and numerous organisms

Cryptococcal antigen is almost invariably detectable in the CSF at high titer

Opening pressure is elevated in up to 25%: important prognostic and therapeutic implications

Diagnosis of cryptococcosis

CSF culture positive India ink positive

Diagnosis of cryptococcosis

Cryptococcal antigen in the serum is highly sensitive and specific for C. neoformans infection

Positive serum cryptococcal antigen titer >1:8 is regarded as presumptive evidence of cryptococcal infection and warrants antifungal therapy, even if infection is not subsequently documented

• Drug(s) of first choice:– Amphotericin B 0.7 mg/kg/d IV +/- flucytosine 100

mg/kg/d x 10-14 days

– then fluconazole 400 mg bid x 2 days, then 400 mg/d x 8-10 wk or itraconazole 400 mg/d x 8-10 wk

• Alternatives:– Fluconazole 400 mg/d x 6-10 wk

– Itraconazole 200 mg tid x 3 days, then 200 mg bid x 6-10 wk

– Fluconazole 400 mg/d plus flucytosine 100 mg/kg/d x 6-10 wk

Cryptococcal Meningitis

Treatment of acute infection

• Drug of first choice: Fluconazole 200 mg up to 400 mg/day

• Alternatives: – Amphotericin B 0.6-1 mg/kg 1-3x/wk

– Itraconazole 400 mg/d or 200 mg oral suspension/d

Suppressive therapy

Cryptococcal Meningitis

• Drug of first choice: Fluconazole 200 mg/d

• Alternative: Itraconazole 200 mg/d or 100 mg oral suspension/d

Prophylaxis (CD4 <50)

การป้�องก�น cryptococcosisในป้ระเทศไทย ข้�อบ่�งชี้��ข้�อบ่�งชี้��

– 4 100 3CD < /mm 4 100 3CD < /mm– เคยเป้�น เคยเป้�น cryptococcosis cryptococcosis มาก�อนมาก�อน

ยาท��ใชี้� ยาท��ใชี้� 400Fluconazole mg weekly 400Fluconazole mg weekly ผู้��ป้�วยท��ได้�ยาต้�านไวร�สและม� ผู้��ป้�วยท��ได้�ยาต้�านไวร�สและม� 4CD 4CD >>

-1 0 0 2 0 0 /-1 0 0 2 0 0 / 33 อย�างน�อย อย�างน�อย 6 6เด้'อน สามารถหย*ด้ยาป้�องก�นได้�เด้'อน สามารถหย*ด้ยาป้�องก�นได้�

Penicilliosis marneffei

CD4 +T cell < 100 cells/mm3

Penicillium marneffei, a dimorphic fungus

Endemic in Southeast Asia (especially Northern Thailand and Southern China)

Potential cause of infection in patients in endemic areas or with a history of travel to endemic areas

Clinical features of 74 hiv-infected patients with disseminated P. marneffei infection

Symptoms number (%) Fever 71 (96) Weight loss 71 (96) Skin lesions 63 (85)

Signs Temperature > 38.3o C 72 (97) Skin lesions 63 (85) Generalized lymphadenopathy 62 (85) Hepatomegaly 48 (65) Splenomegaly 17 (23)

Source: Sirisanthana T, et al. Clin Infect Dis. 1998;26:1107-10

Penicilliosismarneffei

Penicilliosis marneffei

Diagnosis of penicilliosis marneffei

Wright stain : smear from skin lesion, node biopsy, marrow biopsy : 2*3-6 um yeast

Culture from skin, bone marrow,LN Hemoculture

Diagnosis of penicilliosis marneffei

• Drug(s) of first choice:– Amphotericin B 0.7-1.0 mg/kg/d IV or Itraconazole

400 mg/d for 10-12 wk

– Amphotericin B 0.7-1.0 mg/kg/d IV x 2 wk then Itraconazole 400 mg/d for 10 wk

• Alternative: Itraconazole, Ketoconazole or fluconazole

Treatment of acute infection

Penicilliosis marneffei

• Drug(s) of first choice: Itraconazole 200 mg/dSuppressive therapy

Histoplasmosis

Histoplasma capsulatum, a dimorphic fungus

Endemic in the Mississippi and Ohio river valleys of North America, certain areas of Central and South America, and the Caribbean

Mycelial form is found in the soil; particularly soil associated with bird roosts, and caves

Clinical features of histoplasmosis

most common: fever and weight loss, ~ 75% of patients

Respiratory complaints, abdominal pain or gastrointestinal bleeding

5-10% have an acute septic shock-like syndrome, very poor prognosis

Skin lesions: uncommon, molluscum contagiosum-like

Histoplasmosis

• Drug(s) of first choice:– Amphotericin B 0.7-1.0 mg/kg/d IV > 7-14 days

– Itraconazole 300 mg bid x 3 days then 200 mg bid x 10-12 wk

• Alternative: Fluconazole 400 mg/d

Treatment of acute infection

Disseminated histoplasmosis

• Drug(s) of first choice: Itraconazole 200-400 mg/d

• Alternatives: Amphotericin B 1.0 mg/kg q 1-2x /wk or Fluconazole 400 mg/d

Suppressive therapy

การป้�องก�น การป้�องก�น penicilliosis penicilliosisและ และ Histoplasmosis ในป้ระเทศไทย ข้�อบ่�งชี้��

– 41003CD < /mm ( เฉพาะภาคเหน'อ)– เคยเป้�น penicilliosis มาก�อน

ยาท��ใชี้� 200Itraconazole mg qd ผู้��ป้�วยท��ได้�ยาต้�านไวร�สและม� 4CD >

-1 0 0 2 0 0 / 3อย�างน�อย 6เด้'อน สามารถหย*ด้ยาป้�องก�นได้�

Toxoplasmosis

Toxoplasma gondii CD4T cell < 100 cells/mm3

Reactivation of infection Organ involvement

– Brain is the most common site– Lungs– Eye: chorioretinitis– GI– Muscle

Transmission

Ingestion of raw or undercooked meat that contains cysts

Ingestion of water or food contaminated with oocysts

Transplacental transmission

Toxoplamosis Encephalitis (TE)

Cerebritis or brain abscess Diffuse form less common Clinical

– Headache– Neurological deficits– Seizure– Alteration of consciousness– Meningismus – Movement disorders– Neuropsychiatric

Diagnosis of toxoplasmosis

Clinical CT brain scan or MRI Toxoplasma titer Response to treatment Brain biopsy

Toxoplasmosis

Multiple brain lesions

Brain edema Basal ganglia Ring

enhancement

CSF findings in TE

nonspecific mild mononuclear pleocytosis

and mild to moderate elevations in

CSF protein

Toxoplasmosis Treatment

First choice

Pyrimethamine 200 mg x 1 then 75-100 mg /d +

Sulfadiazine 1-1.5 g q 6 hr +

Leukoverin 15 mg qd (if available) for 4-6 wks

Alternative

Pyrimethamine + Leukoverin +

Clindamycin 600 mg q 6 hr

Primary Prophylaxis of Toxoplasmosis

Indications

1. CD4 cell count < 100/mm3

2. Ig G Ab to Toxoplasma

+ve(IDSA)

Regimens for Primary Prophylaxis

First choice TMP-SMX 1 DS qd (AII)Alternative TMP-SMX 1 SS qd (BIII) Dapsone 50 mg qd + Pyrimethamine 50 mg qw + Leukoverin 25 mg qw (if available)

(BI) Dapsone 200 mg qw+ Pyrimethamine 75 mg qw + Leukoverin 25 mg qw (if available)

(BI)

Regimens for Secondary Prophylaxis

First choice Sulfadiazine 500-1000mg qid + Pyrimethamine 25-50 mg/d + Leucoverin 10-25mg/d (AI)Alternative Clindamycin 300-450mg q 6-8 hr + Pyrimethamine 25-50 mg/d + Leucoverin 10-25mg/d (BI)

Summary of toxoplasmosis management

Headache + neurological deficit CT brain scan + serum crypto Ag Mass lesion in brain Empiric treat as Toxoplasmosis Clinical not improve in 2-4 weeks Repeat CT scan Further investigation: brain biopsy

Cytomegalovirus (CMV)

•chorioretinitis •esophagitis•colitis •pneumonia•central nervous system disease

ChorioretinitisChorioretinitis commonly occurs in patients with CD4 <

50 cells/mm³ accounts for 80% to 90% of CMV disease

in patients with AIDS common presenting symptoms include

– decreased visual acuity– perception of floaters– visual field loss

Indirect ophthalmologic screening of patients with a CD4 < 50 cells/mm³ can detect asymptomatic retinitis

ChorioretinitisChorioretinitis

Ophthalmologic exam. reveals large creamy to yellowish-white granular areas with perivascular exudates and hemorrhages

these lesions may occur at either the periphery or center of the fundus.

lesions generally progress within 2 to 3 weeks and can result in blindness

retinitis often begins unilaterally, but progression to bilateral disease is common.

systemic CMV disease involving other viscera may also be present

ChorioretinitisChorioretinitis

DDx: Toxo, Syphilis, HSV, VZV, and TB

Patients with confirmed CMV chorioretinitis should begin treatment promptly

A variety of agents have demonstrated efficacy in delaying time to progression of retinitis

CMV Retinitis

CMV Retinitis

Treatment Ganciclovir Foscarnet

(phosphonoformic acid)

Cidofovir

• Systemic therapy• Local therapy

CMV Retinitis Treatment

Systemic Ganciclovir Induction:

– 5 mg/kg iv over 1 hr q 12 hr for 2-3 wk

Maintenance:– 5 mg/kg iv over 1

hr OD, 5 days/wk– Or 1,000 mg oral tid

Systemic Foscarnet Induction:

– 60 mg/kg q 8 hr for 2-3 wk

Maintenance:– 90 mg/kg per day

CMV Retinitis Treatment

Local Ganciclovir Intravitreal

injection 200-2,000 µg in 0.1 ml

Ganciclovir implant

Local Foscarnet Intravitreal

injection 1.2-2.4 mg in 0.1 ml

CMV Retinitis Treatment

Systemic Treatment Expensive Cover multiple

system infection Systemic side

effect

Local Treatment Invasive Higher drug level Better quality of

life

Mycobacterium avium Complex (MAC) (MAC = M. avium + M. intracellurare )

CD4 T cell < 50 cells/mm3

MAC is the most common pulmonary and disseminated disease ( particularly in HIV/AIDS)

MAC has been isolated from soil, natural water, municipal water system, food , house, dust , and domestic+wild animals

In HIV/AIDS , infection is acquired through ingestion > inhalation

No evidence of person-to-person transmission

Pulmonary MAC

Clinical feature : chronic cough , low grade fever, malaise, hemoptysis

Diagnosis : – CXR : most common pattern : bilateral

lower lobe infiltrate suggestive of miliary spread, alveolar or nodular infiltrate & hilar a/o mediastinal adenopathy

– C/S

Clinical Manifestations and LAB abnormalities of Disseminated MAC in HIV+ve

Fever 120 87 Night sweats 85 78 Diarrhea 92 47 Abdominal pain 54 35Nausea/vomiting 31 26Weight loss 37 38Lymphadenopathy Intra-abdominal 54 37 Mediastinal 49 10Hepatosplenomegaly 38 24Anemia ( Hb < 8.5 gm/dl) 39 85 Serum alkaline phosphatase 38 53

Feature No. of patients % Positive

Disseminated MAC

Dx– Positive culture of non-

pulmonary, normally sterile site– H/C

Treatment Preferred regimen

– Clarithromycin 500 mg bid PO + Ethambutol 15 mg/kg/day PO

– Azithromycin 500-600 mg/day + Ethambutol 15 mg/kg/day PO

– Severe symptom : two drugs above + ciprofloxacin 500–750 PO bid or levofloxacin 500-750 mg qd PO or rifabutin 300 mg/day PO or amikacin iv 10-15 mg/kg/day

MAC Prophylaxis

IndicationHIV+ve patients with CD4<50 cells/mm3

and without MAC bacteremia Rationale

Incidence of MAC bacteremia in HIV +ve with CD4 < 50 cells/mm3

Morbidity and Mortality with disseminated MAC

Proven efficacy of available prophylactic regimens

MAC prophylaxis

50 Rifabutin 300 mg once daily

66 Azithromycin 1200 mg once weekly

69 Clarithromycin 500 mg twice daily

Bacteremia (%)

Regimen

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