HIV II
Update on Opportunistic Infections Prevention and Treatment
Pathophysiology
Depletion of CD-4 cells (T-helper) HIV binds Cell entry cell 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/AIDS idiopathic CD4+ T lymphocytopenia Iatrogenic
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 timeseries 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 histo bartonellosis CMV cryptococcosis
Mycobacterium aviumintracellulare complex (MAC)
Disseminated
FUO
Fever, night sweats, weight loss, diarrhea Anemia, elevated alkaline phosphatase
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
GI Visceral pulmonary
MAC
Findings
Adenopathy Elevated alk phos anemia
Treatment
Macrolide + ethambutol + rifabutin Amikacin ciprofloxacin
Diagnosis
Blood culture Tissue culture Histopathology
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 TB DI’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
Treatment
Erythromycin Tetracycline deriv.
B. henselae and B.
quintana
Bartonellosis
HIV-higher incidence Older cats less likely to transmit Control fleas No rec for primary prophylaxis Consider 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
pneumonitis GI
Gastritis/GU DU colitis
Encephalitis Transverse myelitis Radiculitis
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
CMV
prophylaxis
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/u
CMV-neg or leukopoor irradiated blood if CMV (-)
HIV and diarrhea
Cryptosporidium Microsporidiosis Isospora Giardia bacterial enteric infections
Salmonella Shigella campylobacter Listeria
CMV Cdiff
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 Infections
Prevention
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 cellsmicroscopic appearance of extracellular, adherent parasite
Cryptosporidiosis
prevention
biopsy fecal examination
Modifed AFB Immunohisto stains
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)
Treatment
Azithromycin Paromomycin Octreotide nitazoxanide HAART
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 host endemic 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
histologic sections
Villus atrophy, eosinophil infiltrates, and disorganization of the epithelium
HIV-chronic high-volume watery diarrhea Detection in stool samples difficult, and concentration or flotation methods. AFB +
shown better with Giemsa on histo Cipro better than Bactrim
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
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 > mo. infect enterocytes and proliferate within a supranuclear parasitophorous vacuole.
TABLE 3 -- Diagnostic Workup of HIVRelated 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
PCP histoplasmosis cryptococcosis rhodococcus CMV Pneumococcus
100-fold risk
Nontypable H. flu Pseudomonas
40-fold risk Lowest CD4
HHV-8 Coccidiodomycosis
TABLE 1 -- CAUSES OF RESPIRATORY DISEASE IN PERSONS WITH HIV Very Common Pneumocystis carinii S. pneumoniae H. influenzae MTB * Somewhat Common Pseudomonas aeruginosa Staphylococcus aureus Enteric GNR Histoplasma capsulatum C. neoformans Cytomeglovirus Kaposi's sarcoma Aspergillusspp. Pulmonary lymphoma Congestive heart failure Rare Nocardia asteroides Legionella spp. M. avium complex Toxoplasma gondii Cryptosporidium R. equii Primary pulmonary HTN Lymphocytic interstitial pneumonia (LIP)
PCP
PCP
Symptoms
Incidious onset SOB>cough pneumothorax
Diagnosis
Sputum for DFA Sputum cytology BAL for same Histopathology/stains
Findings
diffuse infiltrates in a perihilar or bibasilar distribution and a reticular or reticulonodular pattern No effusion Elevated LDH SX>>>CXR
Normal in 26%
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
PCP
prophylaxis
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
PCP
prophylaxis
Dapsone Dapsone + pyrimethamine/leucov orin aerosolized pentam (Respirgard II)pregnancy 1st term atovaquone
All BI
Other aerosolized Pentam parenteral pentam oral pyrimethamine/ sulfadoxine oral clinda/primaquine trimetrexate
All CIII
PCP
prophylaxis
Stop when CD4>200 for 3 mo. Restart if CD4<200 Stop 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
THE MOST common endemic mycosis Pulmonary, mucosal, disseminated or CNS Respiratory culture Blood culture Bone marrow biopsy Urine Ag Mississippi valley and Ohio valley + worldwide Normal hosts usually asympto or mild URI-no rx
Some cross reaction More sensitive in dissem disease, esp HIV
Rx ampho, itra
Clin Chest Med - 01-DEC-1996; 17(4): 725-44
Histoplasmosis
Prevention
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 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>200 No data for CD4<200 Repeat in 5 years Repeat when CD4 >200
Tuberculosis
Low threshold of suspicion Lower CD4=atypical presentation Higher mortality Tuberculin 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" 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
Reculture at 2 mo of trx
Extend if still + and cavitary disease
Tuberculosis
prevention
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
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 CD4>200
rifabutin can be sub’d (less data)
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
Molluscum HHV-8 (KS) HPV VZV HSV cryptococcus Bartonella Syphilis Candida Seborrheic dermatitis Folliculitis
Eosinophilic bacterial
Psoriasis Onchomycosis Prurigo nodularis
scabies
Molluscum contagiosum
Papular eruption
Pearly umbilicated
Poxvirus Usually CD4 < 200 Rx 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
VZV
HSV
Very common (>90% of MSM sero+) Severe, erosive disease, proctitis Some need chronic suppression (acyclovir/famcyclovir) Resistance occurs and cross-res w/ganciclovir.
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-meningitis Toxoplasmosis-enhancing PML lymphoma HIV CMV (perivent) EBV
nonenhancing
Cryptococcus
Meningitis
Headache subtle cognitive effects. Occaasional meningeal signs and focal neurologic findings nonspecific presentation is the norm
Diagnosis
CSF Ag sens=100% Need opening pressure
Pulmonary disease Disseminated disease
FUO Adenopathy Skin nodules Organ involvement
Treatment
Ampho + 5FC (GI, hem toxicity) fluconazole
Cryptococcal meningitis
ICP management
>250 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 < 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
Cryptococcus
Prevention
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
Toxoplasmosis
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
Encephalitis
sensorimotor deficits, seizure, confusion, ataxia. Fever, headache common. Multiple ring-enhancing lesions Almost always due to reactivation
Toxoplasma
Treatment
Pyrimethamine 100200 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
Toxoplasma
prophylaxis
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
Toxoplasma
primary 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)
Toxoplasma
primary prophylaxis
Stop primary px when CD4 > 200 for 3 months stop secondary restart when CD4 drops <100 again
Toxoplasma
secondary prophylaxis
After initial therapy completed Pyrimethamine plus sulfadiazine pyrimethamine 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 PCP MAC Toxo PCP MAC toxo Crypto Type of prophylaxis Primary CD4 limit 200 100 200 200 100 200 100-200 Length >3 months Strength of rec AI AI AI BII CIII CIII CIII
Secondary
>3months > 6mo plus 12 months HAART and no sx >6 months, completed rx and no sx >6 months, completed rx and no sx
What’s new?
Drug interactions Immunization guidelines HHV-8 transmission emphasized 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