1. Update on Opportunistic Infections Prevention and Treatment
HIV II
Update on Opportunistic Infections
Prevention and Treatment

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

4. CD4-deficiency Direct mechanisms Indirect 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

5. CD4 depletion syndromes
HIV/AIDS
idiopathic CD4+ T lymphocytopenia
Iatrogenic
Corticosteroids
Immunosuppresants

6. 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

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

8. 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 ; 18(3):421.

9. 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.

10. HIV and fever Disseminated MAC Disseminated histo bartonellosis CMV
before HAART, most common cause of FUO in advanced AIDS.
Disseminated histo
bartonellosis
CMV
cryptococcosis

11. 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

12. MAC Findings Diagnosis Treatment Adenopathy Elevated alk phos anemia
Blood culture
Tissue culture
Histopathology
Treatment
Macrolide + ethambutol + rifabutin
Amikacin
ciprofloxacin

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

14. 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

15. 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

16. Bartonella Treatment Manifestations B. henselae and B. quintana
Bacillary angiomatosis (BQ)
Lymphadenitis (BH)
Hepatosplenic disease (BH)
peliosis hepatis GI
Brain
neuropsych
bone
B. henselae and B. quintana
Treatment
Erythromycin
Tetracycline deriv.

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

18. CMV Risk groups Test IgG if lower risk group % IgG positive MSM IDU
Childcare exposure
Test IgG if lower risk group
Not IDU/MSM
% IgG positive
Varies by country

19. CMV Manifestations pneumonitis FUO GI pancytopenia CNS Gastritis/GU DU
Retinitis
Blurred vision
scotomata
field cuts
Encephalitis
Transverse myelitis
Radiculitis
pneumonitis GI
Gastritis/GU DU
colitis

20. CMV Diagnosis Treatment Serology-not helpful Valganciclovir
Tissue histopathology
Molecular diagnostics
Antigen
PCR
Treatment
Valganciclovir
Ganciclovir 5 mg/kg IV bid × days
Foscarnet 60 mg/kg IV q8h or 90 mg/kg IV q12h × days
Cidofovir 5 mg/kg IV weekly × 2 then every other week
Implants

21. CMV prophylaxis Primary Secondary
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> mo
Continue regular f/u
CMV-neg or leukopoor irradiated blood if CMV (-)

22. HIV and diarrhea Cryptosporidium Microsporidiosis Isospora Giardia
bacterial enteric infections
Salmonella
Shigella
campylobacter
Listeria
CMV
Cdiff

23. 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

24. HIV and diarrhea Stool studies Thorough history Medication review
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

25. 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

26. 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

27. Cryptosporidiosis prevention
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)

28. 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

29. 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

30. Isospora histologic sections shown better with Giemsa on histo
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

31. 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

32. 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.

34. HIV and pneumonia PCP histoplasmosis cryptococcosis rhodococcus CMV
Pneumococcus
100-fold risk
Nontypable H. flu
Pseudomonas
40-fold risk
Lowest CD4
HHV-8
Coccidiodomycosis

36. PCP

37. PCP Diagnosis Symptoms Sputum for DFA Sputum cytology Findings
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

38. 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

39. 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

40. PCP prophylaxis 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

41. 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.

42. 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

43. Clin Chest Med - 01-DEC-1996; 17(4): 725-44

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

45. 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

46. 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

49. 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

54. 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
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 contraindicated
Vague guidelines for repeating PPD
yearly if “high risk”
repeat when CD4>200

55. 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)

56. Med Clin North Am - 01-Nov-2001; 85(6): 1461-91,

57. HIV and rash Molluscum HHV-8 (KS) HPV VZV HSV cryptococcus Bartonella
Syphilis
Candida
Seborrheic dermatitis
Folliculitis
Eosinophilic
bacterial
Psoriasis
Onchomycosis
Prurigo nodularis
scabies

58. Molluscum contagiosum
Papular eruption
Pearly
umbilicated
Poxvirus
Usually CD4 < 200
Rx liquid nitrogen

59. 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

60. Human papillomavirus Manifestations: Genital epithelial cancer
Condyloma acuminata
Plantar warts
Facial
Periungual
Genital epithelial cancer
Twice yearly screening, then annual in women
Follow NCI guidelines
Screening for men being developed

61. Herpes HSV VZV Very common (>90% of MSM sero+)
Prior frequent ADI, occurs at CD
Dermatomal, ocular, disseminated
No effective secondary prevention recs
Avoid exposure
Vaccinate relatives
VZIG if exposed and negative
HSV
Very common (>90% of MSM sero+)
Severe, erosive disease, proctitis
Some need chronic suppression (acyclovir/famcyclovir)
Resistance occurs and cross-res w/ganciclovir.

62. Candida Infections Responds quickly to therapy
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

63. HIV and headache Cryptococcus-meningitis Toxoplasmosis-enhancing PML
lymphoma
HIV
CMV (perivent)
EBV
nonenhancing

64. Cryptococcus Diagnosis Treatment Meningitis Pulmonary disease
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

65. 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

66. Cryptococcus Prevention
Primary prophylaxis effective but generally not rec
Secondary until CD4> mo. and no sx (only CIII rec)
Fluconazole (AI)
Restart at <

67. 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.

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

69. Toxoplasma Treatment
Pyrimethamine mg then 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

70. 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

71. 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)

72. Toxoplasma primary prophylaxis
Stop primary px when CD4 > 200 for 3 months
stop secondary
restart when CD4 drops <100 again

73. 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

74. What’s new?

75. What’s new? Drug interactions Immunization guidelines
HHV-8 transmission
emphasized HCV screening

76. References
Opportunistic infections in HIV disease: down but not out. Sax PE - Infect Dis Clin North Am - 01-JUN-2001; 15(2):
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):
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