HIV II

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HIV II

• Update on Opportunistic Infections
• Prevention and Treatment

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Pathophysiology

• Depletion of CD-4 cells (T-helper)
• HIV binds
• Cell entry
• cell death

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CD4-deficiency

• Direct mechanisms  
• Accumulation of unintegrated viral DNA
• Interference with cellular RNA processing
• Intracellular gp 120-CD4 autofusion events
• Loss of plasma membrane integrity because of
  viral budding
• Elimination of HIV-infected cells by
  virus-specific immune responses

• Indirect mechanisms  
• Aberrant intracellular signaling events
• Syncytium formation
• Autoimmunity
• Superantigenic stimulation
• Innocent bystander killing of viral
  antigen-coated cells
• Apoptosis
• Inhibition of lymphopoiesis

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CD4 depletion syndromes

• HIV/AIDS
• idiopathic CD4 T lymphocytopenia
• Iatrogenic
• Corticosteroids
• Immunosuppresants

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Opportunistic infections

• For patients taking potent combination
  antiretroviral therapy (ART), beginning in 1996,
  there has been a dramatic decline in the
  incidence of AIDS-related opportunistic
  infections (OIs) such as Pneumocystis carinii
  pneumonia (PCP), disseminated Mycobacterium avium
  complex (MAC), and invasive cytomegalovirus (CMV)
  disease

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Treatment Guidelines

• 2001 USPHS/IDSA Guidelines for the Prevention of
  Opportunistic Infections in Persons Infected with
  HIV
• Treatment of Tuberculosis - June 20, 2003

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Rating Strength of the Recommendation

• A Both strong evidence for efficacy and
  substantial clinical benefit support
  recommendation for use. Should always be offered.
  
• B Moderate evidence for efficacy -- or strong
  evidence for efficacy but only limited clinical
  benefit -- supports recommendation for use.
  Should generally be offered.
• C Evidence for efficacy is insufficient to
  support a recommendation for or against use. Or
  evidence for efficacy might not outweigh adverse
  consequences (e.g., drug toxicity, drug
  interactions) or cost of the chemoprophylaxis or
  alternative approaches. Optional.

• D Moderate evidence for lack of efficacy or for
  adverse outcome supports a recommendation against
  use. Should generally not be offered.
• E Good evidence for lack of efficacy or for
  adverse outcome supports a recommendation against
  use. Should never be offered.

Gross PA, Barrett TL, Dellinger EP, et al.
Purpose of quality standards for infectious
diseases. Clin Infect Dis 1994 18(3)421.
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Quality of evidence supporting the recommendation

• I Evidence from at least one properly randomized,
  controlled trial.
• II Evidence from at least one well-designed
  clinical trial without randomization, from cohort
  or case-controlled analytic studies (preferably
  from more than one center), or from multiple
  time-series studies. Or dramatic results from
  uncontrolled experiments.
• III Evidence from opinions of respected
  authorities based on clinical experience,
  descriptive studies, or reports of expert
  committees.

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HIV and fever

• Disseminated MAC
• before HAART, most common cause of FUO in
  advanced AIDS.
• Disseminated histo
• bartonellosis
• CMV
• cryptococcosis

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Mycobacterium avium-intracellulare complex (MAC)

• Disseminated
• FUO
• Fever, night sweats, weight loss, diarrhea
• Anemia, elevated alkaline phosphatase
• GI
• Visceral
• pulmonary

• Localized"immune reconstitution" illnesses
• biopsies show a granulomatous response
• lymphadenitis (mesenteric, cervical, thoracic)
• can mimic Pott's disease with disease presenting
  in the spine
• Pulmonary

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MAC

• Findings
• Adenopathy
• Elevated alk phos
• anemia
• Diagnosis
• Blood culture
• Tissue culture
• Histopathology

• Treatment
• Macrolide ethambutol rifabutin
• Amikacin
• ciprofloxacin

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MAC

• Sources
• Food
• Water
• soil
• Screening not rec b/c no data for benefit,
  although predicts disease
• No recs for avoidance

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MAC prophylaxis

• Primary CD4 lt 50 until gt100 3 mo. (AI)
• Clarithromycin
• Azithromycin
• Rifabutin (not combo-EI)
• Exclude TB
• DIs
• Secondary for 12 mo and until CD4 no sx and CD4
  gt100 6 mo (BCx neg)
• Macrolide ethambutol, /- rifabutin
• High dose clarithromycin asso. W/higher mortality
  (EI)
• Clofazimine too many ADRs (DII)
• Restart at CD4 lt50-100

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Drug Interactions

• Azithromycin not affected by c P450
• Protease inhibitors
• Increase clarithromycin levels
• Some contraindicated w/rifabutin

• NNRTIs (efavirenz)
• Induce clarithromycin metabolism
• Some contraindicated w/rifabutin

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Bartonella

• Manifestations
• Bacillary angiomatosis (BQ)
• Lymphadenitis (BH)
• Hepatosplenic disease (BH)
• peliosis hepatis
• GI
• Brain
• neuropsych
• bone
• B. henselae and B. quintana

• Treatment
• Erythromycin
• Tetracycline deriv.

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Bartonellosis

• HIV-higher incidence
• Older cats less likely to transmit
• Control fleas
• No rec for primary prophylaxis
• Consider long-term suppression (C-III)

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CMV

• Risk groups
• MSM
• IDU
• Childcare exposure
• Test IgG if lower risk group
• Not IDU/MSM
• IgG positive
• Varies by country

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CMV

• Manifestations
• FUO
• pancytopenia
• CNS
• Retinitis
• Blurred vision
• scotomata
• field cuts
• Encephalitis
• Transverse myelitis
• Radiculitis

• pneumonitis
• GI
• Gastritis/GU
• DU
• colitis

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CMV

• Diagnosis
• Serology-not helpful
• Tissue histopathology
• Molecular diagnostics
• Antigen
• PCR

• Treatment
• Valganciclovir
• Ganciclovir 5 mg/kg IV bid 14-21 days
• Foscarnet 60 mg/kg IV q8h or 90 mg/kg IV q12h
  14-21 days
• Cidofovir 5 mg/kg IV weekly 2 then every other
  week
• Implants

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CMVprophylaxis

• Primary
• Can consider if IgG () and CD4 lt50
• Oral ganciclovir or valganciclovir
• Regular optho exams
• Discuss symptoms
• NOT acyclovir/valacyclovir

• Secondary
• Intraocular alone not sufficient
• Valganciclovir
• Consider stopping when CD4gt100-150 6mo
• Continue regular f/u
• CMV-neg or leukopoor irradiated blood if CMV (-)

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HIV and diarrhea

• Cryptosporidium
• Microsporidiosis
• Isospora
• Giardia

• bacterial enteric infections
• Salmonella
• Shigella
• campylobacter
• Listeria
• CMV
• Cdiff

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HIV and diarrhea

• Crampy abdominal pain, bloating, and nausea
  suggest small bowel
• Cryptosporidia
• Microsporidia
• Isospora
• Giardia
• cyclospora)
• MAC.
• High-volume, watery diarrhea with weight loss and
  electrolyte disturbance is most characteristic of
  cryptosporidiosis
• bloody stools with abdominal cramping and fever (
  invasive bacterial pathogen)
• Clostridium difficile
• CMV colitis

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HIV and diarrhea

• Stool studies
• OP
• Trichrome
• AFB
• Immunohisto
• Cdiff
• Thorough history
• Medication review
• Low threshold for flex sig

• Given the availability of effective treatment
  more aggressive evaluation that often includes
  endoscopy has replaced the less invasive
  approach.
• Treatment
• Antimotility agents
• Imodium, Lomotil
• Opium
• Calcium
• octreotide

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Bacterial Enteric InfectionsPrevention

• Seek vet care for animals with diarrhea
• WASH HANDS
• Travel precautions
• Bottled beverages
• Avoid fresh produce
• Avoid ice
• Consider prophylaxis or early empiric therapy
• Cipro 500 qd
• Bactrim

• Avoid
• Reptiles, chicks and ducklings
• Raw eggs
• Raw poultry, meat and seafood
• Unpasteurized dairy products/juices
• Raw seed sprouts
• Soft cheeses
• Deli counters unless can reheat
• Refrigerated meat spreads

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Cryptosporidium

• coccidian protozoan (I. belli, C. cayetanensis,
  and Toxoplasma gondii)
• 5-10 of diarrhea in immunocompetent
• Asymptomatic carriers
• mammalian hosts-cattle, horses, rabbits, guinea
  pigs, mice.
• transmission fecal-oral.

• Waterborne outbreaks due to contamination of
  drinking water
• thick-walled, highly resistant oocyst
• excysts in stomach
• sporozoites infect enterocytes and persist at the
  apical pole of intestinal epithelial
  cells-microscopic appearance of extracellular,
  adherent parasite

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Cryptosporidiosisprevention

• biopsy
• fecal examination
• Modifed AFB
• Immunohisto stains
• Treatment
• Azithromycin
• Paromomycin
• Octreotide
• nitazoxanide
• HAART

• Clarithromycin/rifabutin work, but no data.
• Counsel regarding exposure-avoid feces
• diapers
• young animals (screen BIII)
• water
• boil water when suggested (AI)
• filters (CIII)
• oysters
• bottled (CIII)

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Microsporidiosis

• observed initially in intestinal biopsy specimens
  in 1982
• No disease in normal hosts
• 2 types
• Enterocytozoon bieneusi, reproduces within
  enterocytes
• Encephalitozoon (Septata) intestinalis infects
  epithelial cells and stromal cells of the lamina
  propria and causes systemic infection

• Diagnosis
• Difficult to see by light microscopy-order
  trichrome stain
• Treatment
• Albendazole (for intestinalis)
• Atovaquone
• metronidazole.
• No recs for prevention

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Isospora

• no other known host
• endemic in Brazil, Colombia, Chile, and parts of
  equatorial Africa and southwest Asia.
• seen rarely in normals
• fecal-oral route

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Isospora

• Immunocompetent
• watery diarrhea
• usually clear the infection within about 2 weeks
  
• may persist
• HIV-chronic high-volume watery diarrhea
• Detection in stool samples difficult, and
  concentration or flotation methods. AFB

• histologic sections
• Villus atrophy, eosinophil infiltrates, and
  disorganization of the epithelium
• shown better with Giemsa on histo
• Cipro better than Bactrim

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Cyclospora

• first reported in the 1980s
• endemic in tropical countries and other areas
  w/poor standards of hygiene and water
  purification
• severity related to the degree of
  immunosuppression
• Rx Bactrim

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Cyclospora

• Epidemics attributed to contamination of water
  supplies, fruits, and vegetables
• similar to Cryptosporidium but larger (8 to 10
  mum versus 4 to 5 mum) and AFB
• fecal-oral route
• intermittent watery diarrhea for 3 gt mo.
• infect enterocytes and proliferate within a
  supranuclear parasitophorous vacuole.

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HIV and pneumonia

• PCP
• histoplasmosis
• cryptococcosis
• rhodococcus
• CMV

• Pneumococcus
• 100-fold risk
• Nontypable H. flu
• Pseudomonas
• 40-fold risk
• Lowest CD4
• HHV-8
• Coccidiodomycosis

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PCP
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PCP

• Symptoms
• Incidious onset
• SOBgtcough
• pneumothorax
• Findings
• diffuse infiltrates in a perihilar or bibasilar
  distribution and a reticular or reticulonodular
  pattern
• No effusion
• Elevated LDH
• SXgtgtgtCXR
• Normal in 26

• Diagnosis
• Sputum for DFA
• Sputum cytology
• BAL for same
• Histopathology/stains

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PCP

• TMP 15 mg/kg/d SMX 75 mg/kg/d po or IV 21
  days in 3-4 divided doses for outpatient, 2 DS
  tablets po tid
• rash, fever, gastrointestinal symptoms,
  hepatitis, hyperkalemia, leukopenia, and
  hemolytic anemia
• Steroid (pO2 lt 70 or A-a gradient gt 35)
• TMP-dapsone
• Clinda/primaquine
• Atovaquone
• Trimetrexate/folinic acid
• Iv Pentam
• nausea, infusion-related hypotension,
  hypoglycemia, hypocalcemia, renal failure, and
  pancreatitis

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PCPprophylaxis

• CD4lt200 or history of oral thrush (AII)
• CD4lt14 or other OI (BII)

• Bactrim (AI)
• DS daily (toxo, bacterial pathogens)
• SS daily
• DS TIW (BII)
• rechallenge if rash (desens) - 70 tolerate

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PCPprophylaxis

• Dapsone
• Dapsone pyrimethamine/leucovorin
• aerosolized pentam (Respirgard II)-pregnancy 1st
  term
• atovaquone

• Other aerosolized Pentam
• parenteral pentam
• oral pyrimethamine/ sulfadoxine
• oral clinda/primaquine
• trimetrexate

All BI
All CIII
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PCPprophylaxis

• Stop when CD4gt200 for 3 mo.
• Restart if CD4lt200
• Stop secondary prophylaxis if CD4gt200 unless PCP
  occurred at higher CD4

• Children of HIV mothers need prophylaxis
• Children with PCP can not stop secondary
  prophylaxis.

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Histoplasmosis

• THE MOST common endemic mycosis
• Pulmonary, mucosal, disseminated or CNS
• Respiratory culture
• Blood culture
• Bone marrow biopsy
• Urine Ag
• Some cross reaction
• More sensitive in dissem disease, esp HIV
• Rx ampho, itra

• Mississippi valley and Ohio valley worldwide
• Normal hosts usually asympto or mild URI-no rx

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Clin Chest Med - 01-DEC-1996 17(4) 725-44
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HistoplasmosisPrevention

• Routine skin testing not predictive
• Avoid
• Creating soil/old building dust
• Cleaning chicken coops
• Disturbing bird roosts
• Exploring caves

• Secondary prophylaxis
• Itraconazole
• No data-no rec for stopping
• Primary Prophylaxis
• No proven survival benefit
• Consider in high risk and CD4lt100

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Typical CAP

• Increased mortality with Pneumococcal
• Increased incidence of Pseudomonas
• Bactrim and macrolide prophylaxis prevent resp
  infections, but not rec solely for this reason

• Maintain normal granulocyte count IgG
• Prevention
• Pneumovax
• BII rec if CD4gt200
• No data for CD4lt200
• Repeat in 5 years
• Repeat when CD4 gt200

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Tuberculosis

• Low threshold of suspicion
• Lower CD4atypical presentation
• Higher mortality
• Tuberculin skin testing (TST) negative in 40 of
  patients with disease

• 4-drug therapy initially
• Drug interactions major issue

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Tuberculosis

• New guidelines
• Emphasize DOT and provider responsibility
• Louis Pasteur once said, "The microbe is
  nothing...the terrain everything"
• Reculture at 2 mo of trx
• Extend if still and cavitary disease

• INH--rifapentine once weekly continuation phase
  (Regimens 1c and 2b) is contraindicated
• CD4 cell counts lt100/µl should receive daily or
  three times weekly treatment
• paradoxical flares occur
• Associated w/HAART
• Effusions, infiltrates, enlargement of CNS
  lesions, nodes, fever
• Steroids used

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Tuberculosisprevention

• PPD on diagnosis of HIV (5mm)
• if positive treat
• INH/B6 9 months (AII)
• rifampin 4 months (BIII)
• rif/PZA for 2 months
• hepatic toxicity
• rifabutin can be subd (less data)

• Close contacts should be treated if HIV
• if exposed to MDR TB needs expert advice and PH
• BCG contraindicated
• Vague guidelines for repeating PPD
• yearly if high risk
• repeat when CD4gt200

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Coccidiocomycosis

• Growth is enhanced by bat and rodent droppings.
• Exposure is heaviest in the late summer and fall
• Acute pulm, chronic pulm, dissem, CNS
• more severe in immunosuppressed individuals,
  African Americans, and Filipinos
• 2/3 of immunosuppressed have disseminated disease

• Avoid disturbing native soil
• Diagnose by serology or biopsy
• Blood cultures not usually positive
• Skin test not predictive
• Often refractory to treatement
• Secondary prophylaxis lifelong, too little data
  for stopping (gt100)

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Med Clin North Am - 01-Nov-2001 85(6) 1461-91,
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HIV and rash

• Molluscum
• HHV-8 (KS)
• HPV
• VZV
• HSV
• cryptococcus
• Bartonella
• Syphilis

• Candida
• Seborrheic dermatitis
• Folliculitis
• Eosinophilic
• bacterial
• Psoriasis
• Onchomycosis
• Prurigo nodularis
• scabies

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Molluscum contagiosum

• Papular eruption
• Pearly
• umbilicated
• Poxvirus
• Usually CD4 lt 200
• Rx liquid nitrogen

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HHV-8

• Agent of Kaposis sarcoma
• Vertical transmission occurs
• No screening available
• Antivirals may have some effect
• May be accelerated if infected after HIV
• Advise about prevention

• Manifestations
• Cutaneous
• Mucosal
• Visceral
• GI
• Pulmonary
• other

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Human papillomavirus

• Manifestations
• Condyloma acuminata
• Plantar warts
• Facial
• Periungual

• Genital epithelial cancer
• Twice yearly screening, then annual in women
• Follow NCI guidelines
• Screening for men being developed

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Herpes

• VZV
• Prior frequent ADI, occurs at CD4 200-500
• Dermatomal, ocular, disseminated
• No effective secondary prevention recs
• Avoid exposure
• Vaccinate relatives
• VZIG if exposed and negative

• HSV
• Very common (gt90 of MSM sero)
• Severe, erosive disease, proctitis
• Some need chronic suppression (acyclovir/famcyclov
  ir)
• Resistance occurs and cross-res w/ganciclovir.

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Candida Infections

• Manifestations
• Oral thrush
• Esophageal candidiasis
• Candidal dermatitis
• vulvovaginal
• Treatment
• fluconazole
• Clotrimazole
• Nystatin
• Itraconazole
• Amphotericin (po or iv)

• Responds quickly to therapy
• Primary prophylaxis not rec
• Secondary is optional, prefer early empiric rx
• Azole resistance is an issue

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HIV and headache

• Cryptococcus-meningitis
• Toxoplasmosis-enhancing
• PML
• lymphoma
• HIV
• CMV (perivent)
• EBV

nonenhancing
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Cryptococcus

• Meningitis
• Headache
• subtle cognitive effects.
• Occaasional meningeal signs and focal neurologic
  findings
• nonspecific presentation is the norm
• Pulmonary disease
• Disseminated disease
• FUO
• Adenopathy
• Skin nodules
• Organ involvement

• Diagnosis
• CSF Ag sens100
• Need opening pressure
• Treatment
• Ampho 5FC (GI, hem toxicity)
• fluconazole

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Cryptococcal meningitis

• ICP management
• gt250 mm H2 O was seen in 119 out of 221 patients
• higher titers of cryptococcal antigen
• more severe clinical manifestations
• headache, meningismus, papilledema, hearing loss,
  and pathologic reflexes
• shortened long-term survival
• Desired OP lt 200 mm H2 O or 50 of the initial
  pressure
• Daily lumbar punctures until the pressure is
  stable
• Lumbar drain
• Ventriculoperitoneal shunting
• Corticosteroids are not recommended

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CryptococcusPrevention

• Primary prophylaxis effective but generally not
  rec
• Secondary until CD4gt100-200 6 mo. and no sx (only
  CIII rec)
• Fluconazole (AI)
• Restart at lt100-200

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Toxoplasmosis

• Toxoplasmosis seronegative or toxoplasmosis
  prophylaxis or lesions atypical radiographically
  for toxoplasmosis (single, crosses midline,
  periventricular) CSF exam /- biopsy
• EBV PCR highly correlates with lymphoma
• JCV PCR c/w PML
• toxo PCR diagnostic
• Toxo IgG no prophylaxis Empiric Rx
• Clinical response is usually seen within 7 days
  (and often sooner), and
• radiographic response in 14 days.

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Toxoplasmosis

• Encephalitis
• sensorimotor deficits, seizure, confusion,
  ataxia.
• Fever, headache common.
• Multiple ring-enhancing lesions
• Almost always due to reactivation

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ToxoplasmaTreatment

• Pyrimethamine 100-200 mg then 50-100 mg/d
  folinic acid 10 mg/d sulfadiazine 4-8 g/d for
  at least 6 weeks
• Or sub clinda, azithro, clarithro or atovaquone
• Steroids if mass effect

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Toxoplasmaprophylaxis

• Screen for IgG (BIII)
• if negative, aggressively counsel regarding
  avoidance of cat litter, raw meat (165 deg)
• wash, wear gloves when gardening
• wash vegetables
• keep cats indoors, avoid raw meat foods
• getting rid of or testing the cat is an EIII
  offense!
• CD4 lt100 if seropositive only

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Toxoplasmaprimary prophylaxis

• Trim/sulfa DS qd (AII)
• dapsone/pyrimethamine (BI)
• atovaquone (CIII)
• dapsone, macrolides, pyrimethamine dont work
  (DII)
• Aerosolized pentam definitely doesnt work (EII)

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Toxoplasmaprimary prophylaxis

• Stop primary px when CD4 gt 200 for 3 months
• stop secondary
• restart when CD4 drops lt100 again

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Toxoplasmasecondary prophylaxis

• After initial therapy completed
• Pyrimethamine plus sulfadiazine
• pyrimethamine plus clinda (not for PCP)
• stop when CD4gt200 for 6 months, no symptoms and
  initial therapy completed
• restart if drop below 200

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Whats new?
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Whats new?

• Drug interactions
• Immunization guidelines
• HHV-8 transmission
• emphasized HCV screening

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References

• Opportunistic infections in HIV disease down but
  not out. Sax PE - Infect Dis Clin North Am -
  01-JUN-2001 15(2) 433-55
• Graybill JR, Sobel J, Saag M, et al Diagnosis
  and management of increased intracranial pressure
  in patients with AIDS and cryptococcal
  meningitis. The NIAID Mycoses Study Group and
  AIDS Cooperative Treatment Groups. Clin Infect
  Dis 3047, 2000
• Infectious diarrhea in human immunodeficiency
  virus. Cohen J - Gastroenterol Clin North Am -
  01-SEP-2001 30(3) 637-64
• AMERICAN GASTROENTEROLOGICAL ASSOCIATION PRACTICE
  GUIDELINES. AGA Technical Review Malnutrition
  and Cachexia, Chronic Diarrhea, and Hepatobiliary
  Disease in Patients With Human Immunodeficiency
  Virus InfectionVolume Gastroenterology 111
  Number 6 December 1, 1996
• State-of-the-art review of pulmonary fungal
  infections. Seminars in Respiratory
  Infections.Volume 17 Number 2 June 2002