OIs

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OIs Management in AIDS

• Dr. B.D.Benroy
• Program Officer (STD)
• Kerala State AIDS Control Society,
• Trivandrum.

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CD4 Cell Counts and Opportunistic Infections
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CD4 Cells Risk of OI

• CD4 cells gt500/?L Recurrent vaginal
  candidiasis, PGL
• CD4 cells 200-500/?L Herpes zoster, oral
  candidiasis, cervical intraepithelial neoplasia,
  Kaposi sarcoma, non-Hodgkins lymphoma
• CD4 cells 100-200/?L Pneumocystis pneumonia,
  cryptococcosis, AIDS dementia complex, AIDS
  related wasting
• CD4 cells lt50/?L CMV retinitis, MAI,
  Cryptosporidiosis, progressive multifocal
  leukoencephalopathy, primary CNS lymphoma

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Incidence of OI

• Disease
  Incidence / 100 p y
• All forms of TB 75.9
• Disseminated TB 14.1
  Lymph
  nodal TB 11.4
• Pulmonary TB 10.4
• TB meningitis 3.9
• Other extra pulmonary TB 2.6
• 2. Chronic diarrhea 4.8
• 3. Cryptococcal meningitis 3.7
• 4. PCP 3.6
• 5. Neurological illness related to HIV
  0.9
• 6. Cerebral Toxoplasmosis 0.7

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Common OI in India

• Recurrent bacterial infections
• Tuberculosis
• Chronic diarrhoea
• Candidiasis
• Cryptococcosis
• Pneumocystis carinii pneumonia
• Toxoplasmosis

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Approach to OI

• Degree of immunodeficiency (CD4)
• Prophylactic treatment
• Exposure to potential pathogens
• Clinical syndrome
• Pulmonary complications
• GI complications
• Neurologic complications
• Undifferentiated fever (PUO)

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Pulmonary Complications

• Bacterial pneumonia
• Tuberculosis
• Pneumocystis pneumonia (PCP)

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Pneumocystis Pneumonia

• Symptoms dry cough, dyspnea, fever /-
  subacute onset (1-3 wk) CD4 lt200 cells
• Chest x-ray interstitial infiltrates, ground
  glass appearance normal x-ray in 10
• Diagnosis induced sputum, BAL

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PCP Treatment

• Preferred TMP-SMX (TMP 15 mg/kg/d) x 21 days
• Alternatives TMP dapsone, pentamidine,
  clindamycin primaquine
• Steroids for pt. with severe disease (paO2 lt70
  mm Hg or A-a gradient gt35 mm Hg)
• Maintenance TMP-SMX 1 DS tab od

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Bacterial Pneumonia
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HIV and Tuberculosis - 1

• HIV ? people have ? risk of primary or
  reactivation tb reinfection
• lifetime risk of HIV neg., PPD ? persons
  developing active tb - 10
• risk of developing active tb in HIV ?, PPD ?
  person - 7-10/year

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HIV and Tuberculosis - 2

• Pulmonary TB the commonest form
• Resembles post-primary PTB in early stages
  (fibro-cavitary disease) primary PTB in late
  stages (hilar adenopathy, lower zone infiltrates)
• Extra-pulmonary, disseminated TB mycobacteremia
  seen in advanced stages

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CxR Findings in TB Patients with HIV Infection
Late HIV (severely immuno-compromised)
Early HIV
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PTB in Early Late HIV Infection
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AFB Smear
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Tuberculosis Chest X-ray
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Initiation of Antiretroviral Therapy for Patients
with TB To Start or to Delay?

• Reasons to Start ART
• Decrease morbidity and mortality related to
  HIV/AIDS
• Reasons to delay ART
• Overlapping side effects from ART and anti-TB
  therapy
• Complex drug-drug interactions
• Immune reconstitution inflammatory syndrome
• (paradoxical reactions)
• Difficulties with adherence to multiple
  medications

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HIV Tb Treatment

• Duration of treatment 6-12 months (2HREZ /
  4-10HR)
• Rifampicin contra-indicated with PI/NNRTI
  containing HAART regimens
• Possible options for ART in patients with active
  TB
• defer ART until TB treatment is completed
• defer ART until the continuation phase' of
  treatment for TB, and use HE as continuation.
• treat TB with RIF containing regimen and use
  Efavirenz 2 NRTIs

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HIV Tb Prophylaxis

• Chemoprophylaxis effective (RR 0.41)
• Inefficient in feasibility studies
• Indications PPD ?5 mm, high-risk exposure
• Regimens INH (300 mg/d x 12 mo.), RIF (600 mg/d)
  PZA (25 mg/kg/d) x 2 mo.

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GI Complications Syndromic Approach

• Odynophagia
• Diarrhoea
• Jaundice, RUQ pain, hepatomegaly

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Odynophagia

• OI or tumor
• common Candida spp.
• less common CMV, HSV, aphthous ulcers
• rare TB, MAI, histoplasmosis, cryptosporidia,
  KS, lymphoma
• GERD
• Medications
• ddC, AZT, tetracycline, NSAIDs, ASA

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Oral Candidiasis

• Symptoms thrush, sore mouth
• Pseudomembranous, atrophic, hyper-plastic,
  angular cheilitis
• Treatment Nystatin, Fluconazole

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Oesophageal Candidiasis

• 1/3 of AIDS pts develop esophageal symptoms
  (dys-phagia, odynophagia) 50-70 due to Candida
  oral thrush in 50-70
• Usually treated empirically endo-scopy biopsy,
  with HPE cultures, if no response in 7-10 days

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Chronic Diarrhoea

• Occurs in 60-90 of pt. with HIV infection
• Presenting symptom in 1/3
• OIs most common cause
• Many pt. have no likely microbial pathogen
• Enteric infections not always associated with
  diarrhoea

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Chronic diarrhoea

• PROTOZOAL
• Isospora belli
• Cryptosporidia parvum
• Microsporidia
• Giardia lamblia
• AIDS ENTEROPATHY

• BACTERIAL
• MAC
• Salmonellosis
• Clostridium
• Campylobacter
• VIRAL
• CMV
• Adenovirus
• HSV

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Diarrhoea Management

• DIAGNOSIS
• stool ova parasites x 3 days
• stool culture
• small-bowel biopsy
• colonoscopy with biopsy

• TREATMENT
• Cryptosporidia paromomycin azithromycin
• Isospora TMP-SMX
• Microsporidia Albendazole
• HAART
• Empiric therapy

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Jaundice

• Hepatitis
• drug induced
• ethanol use
• HBV, HCV
• MAI
• Acalculous cholecystitis and cholangitis
• CMV
• cryptosporidium
• microsporidium

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HIV and the Nervous System

• HIV enters the brain immediately after infection,
  is present throughout the course of the disease,
  and, can potentially involve all levels of the
  nervous system - meninges, brain, spinal cord,
  cranial peripheral nerves, skeletal muscle
• Neurologic disease is the first manifestation of
  symptomatic HIV infection in 10-20 of persons
• 60 of patients with advanced HIV disease will
  have clinically evident neurologic dysfunction
  during the course of their illness
• Autopsy studies of patients with advanced HIV
  disease have demonstrated pathologic
  abnormalities of the nervous system in 75-90 of
  cases

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Neurologic Complications of HIV Infection

• HIV Related
• Acute aseptic meningitis
• Chronic meningitis
• HIV encephalopathy (AIDS dementia)
• Vacuolar myelopathy
• Peripheral neuropathy (sensory)
• Myopathy

• O I
• Cryptococcal meningitis
• Cerebral toxoplasmosis
• CMV retinitis encephalitis
• PML
• Primary CNS lymphoma
• TB
• Syphilis

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Neurological Complications

• Global cerebral syndromes
• Chronic meningitis / meningo-encephalitis
  cryptococcosis, TB, syphilis
• Focal cerebral lesions
• Toxoplasma encephalitis, primary CNS lymphoma,
  Progressive Multifocal Leukoencephalopathy (PML)
• Cognitive decline
• Myelopathy
• Peripheral neuropathy

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Cryptococcal Meningitis

• Subacute meningo-encephalitis
• Average duration of symptoms 30 days
• Clinical manifestations
• headache (90), fever (60-80), stiff neck
  (40-45), seizures (5-10) CD4 lt100/?L
• Predictors of poor outcomes coma, high opening
  pressure (gt250 mm), WBClt20 cells/mm3, India ink
  preparation cryptococci isolated from
  extra-neural sites
• Diagnosis confirmed by CSF examination with India
  ink (74-88), Crypto Ag serum/CSF (99), CSF
  culture

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Cryptococcus neoformans
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Cryptococcal Meningitis Therapy

• Acute Ampho B (0.7 mg/kg/d) 5-FC 25 mg/kg QID
  x 14 days then Fluconazole 400 mg/d for 8-10
  weeks
• Maintenance Fluconazole 200 mg/d x lifelong
  maybe D/C with immune reconstitution with HAART
  
• Repeated lumbar puncture for elevated ICP (OP
  gt250 mm)
• Steroid treatment associated with treatment
  failure death hence, not recommended

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Neurosyphilis

• Asymptomatic
• Syphilitic meningitis
• Meningo-vascular
• Parenchymal GPI, tabes dorsalis, gumma
• Occular uveitis, chorio-retinitis, optic
  neuritis
• Otologic S-N hearing loss

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Evaluation of CSF for Neurosyphilis

• Any HIV seropositive patient with neurologic,
  ophthalmic, or otologic signs or symptoms
• All patients who fail treatment
• HIV-infected patients with late latent syphilis
  of gt1 year duration or with syphilis of unknown
  duration

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Neurosyphilis Diagnosis

• Positive CSF VDRL with abnormal CSF establishes
  the diagnosis of latent neurosyphilis
• Sensitivity of CSF VDRL only 70
• CSF pleocytosis (usually 10-400 cells/mm3) and
  mildly elevated protein (46-200 mg/dL) positive
  CSF VDRL positive peripheral syphilis serology
• Treatment Pen G 10 L units Q4H i.v. x 10 days

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Toxoplasma Encephalitis

• Toxoplasma gondii, an obligate intracellular
  protozoan commonest cause of CNS mass lesion in
  AIDS incidence 5-20 CD4 lt100/?L
• Clinical presentation focal neurological
  deficits (50-89), seizures (15-20), fever
  (56), generalized cerebral dysfunction
  (confusion, coma), neuropsychiatric
  manifestations
• CT/MRI multiple ring-enhancing lesions located
  in frontal, parietal lobes and/or basal ganglia
  lesions often at corticomedullary junction MRI
  more sensitive than CT
• Serum Toxoplasma IgG usually positive (97)

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Toxoplasma Encephalitis

• Diagnosis is presumptive based on clinical
  presentation, characteristic lesions, risk strata
  positive serology
• Presumptive diagnosis confirmed by tissue sample
  or response to TOXO therapy in appropriate time
  frame
• 86 patients show clinical improvement by day 7
  of treatment 95 show radiographic improvement
  by day 14
• Failure to respond within 14 days - consider
  alternative diagnosis indication for brain biopsy

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Toxoplasma Encephalitis

• Treatment (for at least 6 weeks, 80-90
  response)
• Acute Sulfadiazine (4-6 gm/d) or Clindamycin
  (600 mg q6h Pyrimethamine (100-200 mg x 1 dose
  then 50-75mg/d) with folinic acid (10-20 mg/d)
• Alternatives macrolides (azithromycin,
  clarithromycin) pyrimethamine and folinic
  acid TMP-SMX
• Maintenance Pyrimethamine 25-50 mg/day SD
  0.5-1.0 G Q6H (life long)
• Consider stopping in patients who have completed
  primary treatment, are asymptomatic, and have
  sustained (gt6 months) increase in CD4 cell count
  to gt200/µL with HAART
• Steroids for cerebral edema mass effect

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AIDS Dementia

• CD4 100-200 cells/?L
• Slowly progressive
• Acquired, persistent cognitive decline, with
  motor behavioural changes
• Neurologic exam alert, with non-focal or diffuse
  signs
• CSF non-specific
• CT/MRI cerebral atrophy, ventricular dilatation
• Therapy HAART include drugs which cross BBB

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Progressive Multifocal Leukoencephalopathy

• Multifocal demyelination caused by JC-virus
• Relatively rapidly progressive neurologic
  syndrome over weeks or months
• Cognitive dysfunction, ataxia, aphasia, cranial
  nerve deficits, hemiparesis or quadriparesis, and
  eventually coma
• Typical CT abnormalities include single or
  multiple hypodense, non-enhancing cerebral white
  matter lesions

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Neuropathy

• Distal symmetric polyneuropathy (DSPN)
• Mononeuropathy multiplex
• Chronic inflammatory demyelinating polyneuropathy
  
• Progressive lumbosacral polyradiculopathy (CMV)

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D S P N

• Most common type of neuropathy
• Symptoms tingling, numbness, burning pain in
  the feet, ascending over time.
• Exam bilateral depressed ankle reflexes loss of
  vibration sense decreased appreciation of
  temperature distally motor weakness mild
• Diagnosis of exclusion

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Vacuolar Myelopathy

• Pathology non-inflammatory vacuolation of
  myelin, particularly in the lateral and posterior
  columns of the spinal cord
• Upper thoracic cord affected most commonly
• Clinically pathologically identical to subacute
  combined degeneration (B12 deficiency)
• Subacute progression of motor (spastic
  paraparesis, brisk knee reflex absent ankle
  reflex)) and sensory deficits over several months

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I R I S

• OI - the hallmark of immune suppression caused by
  HIV
• PLWHA may have active co-infections that are
  sub-clinical due to the lack of host inflammatory
  responses
• Reconstitution of the immune system during the
  initial months of HAART may result in the
  development of overt clinical manifestations of
  these co-infections, as restoration of CD4 T
  lymphocytes permits inflammatory responses to be
  mounted - Immune Reconstitution Inflammatory
  Syndrome (IRIS)

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Case 1 Initial Presentation

• 35-year old man with HIV-1 infection (CDC stage
  C3) presented in January 2001 with
• tuberculous lymphadenitis (cervical)
• oesophageal candidiasis
• pruritic papular eruptions
• seborrhoeic dermatitis
• recurrent dermatophyte infections
• CD4 cell count was 50 cells/?l (4) (FAC Scan,
  Becton Dickinson)
• Viral load was 2,66,370 HIV-1 RNA copies/ml
  (Amplicor HIV-1, Roche Systems)

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Case 1 Clinical Course

• The patient was started on HAART in October 2002
  (d4T, 3TC, NVP) which he tolerated well
• Fifteen days after starting therapy the patient
  developed skin lesions - multiple erythematous
  mildly edematous hypoaesthetic to anaesthetic
  plaques on the trunk and extremities
• The left common peroneal nerve and both cutaneous
  branches of the common peroneal nerves were
  enlarged and non-tender

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Case 1 - Skin Lesions
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Case1 - Investigations

• Slit skin smears from the plaques and normal skin
  were negative for acid fast bacilli
• Skin biopsy from the edematous plaque on the
  thigh was consistent with borderline tuberculoid
  leprosy in type I reaction
• CD4 cell count repeated was 112 cells/?l
• Viral load lt400 HIV-1 RNA copies/ml

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Case 1 - Management

• The patient was started on anti leprosy
  chemotherapy with WHO MB MDT regimen, chloroquine
  and a tapering course of steroids (prednisolone),
  with which there was flattening of the skin
  lesions and decreasing erythema
• HAART was continued unchanged during this period

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Case 1 Skin Lesions After Treatment
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Case 2 Initial Presentation

• 34-yr old man known to have HIV-1 infection was
  admitted with severe (paO2 54.2 mm Hg) PCP
• CxR HRCT thorax showed bilateral, diffuse
  interstitial infiltrates
• BAL fluid showed P carinii cysts
• CD4 count was 110 cells/µl (8) VL 2,30,840
  HIV-1 RNA copies/ml
• Marked resolution of symptoms, signs and
  radiological appearance with a 21-day course of
  co-trimoxazole and steroids

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Case 2 Clinical Course

• 11 days after starting PCP therapy, he was
  started on HAART (AZT, 3TC, EFV)
• 13 days later, he developed high-grade fever and
  mild cough with scanty expectoration
• CxR showed marked worsening of the infiltrates
• Induced sputum examination and blood cultures did
  not reveal any pathogens
• CD4 repeated was 260 cells/µl
• Since he remained febrile after one week of
  NSAID, he was started on corticosteroids (x 1
  week) with marked symptomatic improvement
• HAART was continued uninterrupted

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Case 2 Chest X-Rays
Oct 14, 2002
Nov 12, 2002
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Case 3 Initial Presentation

• 35-year old male with HIV-1 infection (CDC Stage
  3C) presented in Jan 2001 with
• Isosporiasis
• Wasting syndrome
• CD4 T cells 42/µl
• VL 2,30,508 HIV-1 RNA copies/ml
• HAART (IDV, AZT, 3TC) in May 2001

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Case 3 Clinical Course

• Nov 2001 recurrent diarrhea, cough with
  expectoration, left-sided chest pain
• Stool o p Isospora belli
• Sputum AFB smear numerous AFB
• Treated with ATT (2SHEZ/10HE) and co-trimoxazole
• HAART continued uninterrupted

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Case 3 Chest X-Rays
Jan 2003
Nov 2002
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OI During HAART

• OI that develop after starting HAART divided into
  three groups
• Sub-clinical infections unmasked by immune
  reconstitution (IRIS)
• OI among patients with suppressed HIV RNA and CD4
  cell counts gt200/µl (incomplete immune
  reconstitution)
• OI among patients experiencing virologic
  immunologic failure

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HAART in Acute OI

• Starting HAART in ART-naïve patient with acute OI
• No specific therapy for OI (e.g.
  cryptosporidiosis, PML) start HAART as soon as
  possible
• Specific therapy available for OI (PCP, M tb,
  cryptococcal meniingitis) await initial response
  to OI treatment

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THANK YOU
HAVE A NICE DAY