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HIV II
Update on Opportunistic InfectionsPrevention and Treatment
Pathophysiology
Depletion of CD-4 cells (T-helper)
HIV bindsCell entrycell death
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
CD4 depletion syndromes
HIV/AIDSidiopathic CD4+ T lymphocytopeniaIatrogenic
Corticosteroids Immunosuppresants
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
Treatment Guidelines
2001 USPHS/IDSA Guidelines for the Prevention of Opportunistic Infections in Persons Infected with HIV
Treatment of Tuberculosis - June 20, 2003
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.
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.
HIV and fever
Disseminated MAC before HAART, most common cause of
FUO in advanced AIDS.Disseminated histobartonellosisCMVcryptococcosis
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
MAC
Findings Adenopathy Elevated alk phos anemia
Diagnosis Blood culture Tissue culture Histopathology
Treatment Macrolide +
ethambutol + rifabutin
Amikacin ciprofloxacin
MAC
Sources Food Water soil
Screening not rec b/c no data for benefit, although predicts disease
No recs for avoidance
MAC prophylaxis
Primary CD4 < 50 until >100 3 mo. (AI) Clarithromycin Azithromycin Rifabutin (not combo-EI)
Exclude TBDI’s
Secondary for 12 mo and until CD4 no sx and CD4 >100 6 mo (BCx neg) Macrolide + ethambutol, +/- rifabutin High dose clarithromycin asso. W/higher mortality (EI) Clofazimine too many ADR’s (DII)
Restart at CD4 <50-100
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
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.
Bartonellosis
HIV-higher incidenceOlder cats less likely to transmitControl fleasNo rec for primary prophylaxisConsider long-term suppression (C-
III)
CMV
Risk groups MSM IDU Childcare exposure
Test IgG if lower risk group
Not IDU/MSM
% IgG positive Varies by country
CMV
Manifestations FUO pancytopenia CNS
Retinitis• Blurred vision • scotomata • field cuts
EncephalitisTransverse myelitisRadiculitis
pneumonitis GI
Gastritis/GUDUcolitis
CMV
Diagnosis Serology-not helpful Tissue
histopathology Molecular
diagnosticsAntigenPCR
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
CMVprophylaxis
Primary Can consider if IgG
(+) and CD4 <50 Oral ganciclovir or
valganciclovir Regular optho exams Discuss symptoms NOT
acyclovir/valacyclovir
Secondary Intraocular alone not
sufficient Valganciclovir Consider stopping
when CD4>100-150 6mo
Continue regular f/uCMV-neg or
leukopoor irradiated blood if CMV (-)
HIV and diarrhea
CryptosporidiumMicrosporidiosisIsosporaGiardia
bacterial enteric infections Salmonella Shigella campylobacter Listeria
CMVCdiff
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
HIV and diarrhea
Stool studies O&P 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
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
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
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)
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
Isospora
no other known hostendemic in Brazil, Colombia, Chile,
and parts of equatorial Africa and southwest Asia.
seen rarely in normals fecal-oral route
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
Cyclospora
first reported in the 1980sendemic in tropical countries and
other areas w/poor standards of hygiene and water purification
severity related to the degree of immunosuppression
Rx Bactrim
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 routeintermittent watery diarrhea for 3 > mo. infect enterocytes and proliferate within a
supranuclear parasitophorous vacuole.
TABLE 3 -- Diagnostic Workup of HIV-Related Chronic Diarrhea
Stool tests
Bacterial culture (to detect Salmonella species and so on)
Ova and parasite examination (Giardia lamblia and so on)
C. difficile toxin assay
Modified acid-fast stain or immunofluorescence kit (cryptosporidia)
Modified trichrome stain (microsporidia)
Add blood cultures if febrile (bacteria, mycobacteria)
Flexible sigmoidoscopy with mucosal biopsies
Light microscopy (mycobacteria, CMV, cryptosporidia)
Mycobacterial culture (mycobacteria)
Upper endoscopy with duodenal biopsies
Light microscopy (CMV, mycobacteria, cryptosporidia, microsporidia)
Mycobacterial culture (mycobacteria)
± electron microscopy (microsporidia)
HIV and pneumonia
PCPhistoplasmosiscryptococcosisrhodococcusCMV
Pneumococcus 100-fold risk
Nontypable H. fluPseudomonas
40-fold risk Lowest CD4
HHV-8Coccidiodomycosi
s
TABLE 1 -- CAUSES OF RESPIRATORY DISEASE IN PERSONS WITH HIV
Very Common Somewhat Common Rare
Pneumocystis carinii Pseudomonas aeruginosa Nocardia asteroides
S. pneumoniae Staphylococcus aureus Legionella spp.
H. influenzae Enteric GNR M. avium complex
MTB * Histoplasma capsulatum Toxoplasma gondii
C. neoformans Cryptosporidium
Cytomeglovirus R. equii
Kaposi's sarcoma Primary pulmonary HTN
Aspergillusspp. Lymphocytic interstitial pneumonia (LIP)
Pulmonary lymphoma
Congestive heart failure
PCP
PCP
Symptoms Incidious onset SOB>cough pneumothorax
Findings diffuse infiltrates in a
perihilar or bibasilar distribution and a reticular or reticulonodular pattern
No effusion Elevated LDH SX>>>CXR
Normal in 26%
Diagnosis Sputum for DFA Sputum cytology BAL for same Histopathology/
stains
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 < 70 or A-a gradient > 35) TMP-dapsone Clinda/primaquine Atovaquone Trimetrexate/folinic acid Iv Pentam
nausea, infusion-related hypotension, hypoglycemia, hypocalcemia, renal failure, and pancreatitis
PCPprophylaxis
CD4<200 or history of oral thrush (AII)
CD4%<14 or other OI (BII)
Bactrim (AI) DS daily (toxo,
bacterial pathogens)
SS daily DS TIW (BII) rechallenge if rash
(desens) - 70% tolerate
PCPprophylaxis
DapsoneDapsone +
pyrimethamine/leucovorin
aerosolized pentam (Respirgard II)-pregnancy 1st term
atovaquone
Other aerosolized Pentam
parenteral pentamoral
pyrimethamine/ sulfadoxine
oral clinda/primaquine
trimetrexateAll BI All CIII
PCPprophylaxis
Stop when CD4>200 for 3 mo.
Restart if CD4<200Stop secondary
prophylaxis if CD4>200 unless PCP occurred at higher CD4
Children of HIV mothers need prophylaxis
Children with PCP can not stop secondary prophylaxis.
Histoplasmosis
Mississippi valley and Ohio valley + worldwide
Normal hosts usually asympto or mild URI-no rx
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
Clin Chest Med - 01-DEC-1996; 17(4): 725-44
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
stoppingPrimary
Prophylaxis No proven survival
benefit Consider in high
risk and CD4<100
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 CD4>200No data for CD4<200Repeat in 5 yearsRepeat when CD4
>200
Tuberculosis
Low threshold of suspicion
Lower CD4=atypical presentation
Higher mortalityTuberculin skin
testing (TST) negative in 40% of patients with disease
4-drug therapy initially
Drug interactions major issue
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 <100/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
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 sub’d (less data)
Close contacts should be treated if HIV+
if exposed to MDR TB needs expert advice and PH
BCG contraindicatedVague guidelines for
repeating PPD yearly if “high risk” repeat when CD4>200
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 (>100)
Med Clin North Am - 01-Nov-2001; 85(6): 1461-91,
HIV and rash
MolluscumHHV-8 (KS)HPVVZVHSVcryptococcusBartonellaSyphilis
CandidaSeborrheic dermatitisFolliculitis
Eosinophilic bacterial
PsoriasisOnchomycosisPrurigo nodularis scabies
Molluscum contagiosum
Papular eruption Pearly umbilicated
PoxvirusUsually CD4 < 200Rx liquid nitrogen
HHV-8
Agent of Kaposi’s 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
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
Herpes
HSV Very common (>90%
of MSM sero+) Severe, erosive
disease, proctitis Some need chronic
suppression (acyclovir/famcyclovir)
Resistance occurs and cross-res w/ganciclovir.
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
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
HIV and headache
Cryptococcus-meningitisToxoplasmosis-enhancingPMLlymphomaHIVCMV (perivent)EBV
nonenhancing
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 sens=100% Need opening
pressure
Treatment Ampho + 5FC (GI,
hem toxicity) fluconazole
Cryptococcal meningitis
ICP management >250 mm H2 O was seen in 119 out of
221 patientshigher titers of cryptococcal antigen more severe clinical manifestations
• headache, meningismus, papilledema, hearing loss, and pathologic reflexes
• shortened long-term survival Desired OP < 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
CryptococcusPrevention
Primary prophylaxis effective but generally not rec
Secondary until CD4>100-200 6 mo. and no sx (only CIII rec) Fluconazole (AI) Restart at <100-200
1. 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
2. Toxo IgG + & no prophylaxis: Empiric Rx• Clinical response is usually seen within 7 days (and
often sooner), and • radiographic response in 14 days.
Toxoplasmosis
Toxoplasmosis
Encephalitis sensorimotor deficits, seizure,
confusion, ataxia. Fever, headache common. Multiple ring-enhancing lesions Almost always due to reactivation
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
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 <100 if seropositive only
Toxoplasmaprimary prophylaxis
Trim/sulfa DS qd (AII)dapsone/pyrimethamine (BI)atovaquone (CIII)dapsone, macrolides, pyrimethamine
don’t work (DII)Aerosolized pentam definitely
doesn’t work (EII)
Toxoplasmaprimary prophylaxis
Stop primary px when CD4 > 200 for 3 months
stop secondaryrestart when CD4
drops <100 again
Toxoplasmasecondary prophylaxis
After initial therapy completedPyrimethamine plus sulfadiazinepyrimethamine plus clinda (not for
PCP)stop when CD4>200 for 6 months, no
symptoms and initial therapy completed
restart if drop below 200
What’s new?
Disease Type ofprophylaxis
CD4 limit Length Strength ofrec
PCP Primary 200 >3 months AIMAC 100 AIToxo 200 AI
PCP Secondary 200 >3months BIIMAC 100 > 6mo plus 12 months
HAART and no sxCIII
toxo 200 >6 months, completed rx and no sx
CIII
Crypto 100-200 >6 months, completed rx and no sx
CIII
What’s new?
Drug interactionsImmunization guidelinesHHV-8 transmissionemphasized HCV screening
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 30:47, 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