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HIV and Opportunistic Infections
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HIV and Opportunistic Infections
Vidhu Kariyawasam, MD
Assistant Professor of Medicine
Infectious Diseases and Global Medicine
University of Florida College of Medicine, Gainesville
Faculty, North Florida AETC
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Disclosures
The activity planners and speaker do not have any financial relationships with commercial entities to disclose.
The speaker will not discuss any off-label use or investigational product during the program.
This slideset has been peer-reviewed to ensure that there are no conflicts of interest represented in the presentation.
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Session Objectives
Recognize the most common opportunistic infections (OIs)
Discuss prophylaxis and treatment of common OIs
Describe types of exposures and ways to prevent OIs
Adherence included in this last point
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Definition: Opportunistic Infection (OI)
Infection by a microorganism that normally does not cause disease but becomes pathogenic when the body's immune system is impaired and unable to fight off infection
Frequently a reactivation of an infection acquired in the past which was controlled when immune system was functional (latent infection)
Can occur de novo
Typically caused by a low virulence organism that becomes overwhelming due to poor cell mediated immunity
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CD4 Cells
Type of white blood cell involved in cell mediated immunity
Normal: 500 - 1500 CD4 cells/mm3
Determines OI risk -Highest risk for HIV related infections occurs with CD4 < 200
No longer used to determine need to start antiretroviral therapy (ART)
Directs management: in terms of urgency to start therapy and potential use of prophylaxis medications to prevent OI's
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HIV Life Cycle
This is a CD4 cell , The HIV virus attatches on to the CD4 cell and using cell material makes more copies , over time the CD4 cell dies
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Typical Course of Untreated HIV- Infection
Munier ML and Kelleher AD.
Immunol Cell Biol. 2007 Jan;85(1):6-15. Epub 2006 Dec 5
CDC.gov. Revised surveillance case definition for HIV Infection United States, 2015. MMWR Recomm Rep. 2014;63(RR-03):1-10.
Opportunistic Infection Risk
< 500
Tuberculosis
< 200
Pneumocystisis jirovecii pneumonia (PCP)
< 100
Toxoplasmosis
Cryptococccal meningitis
< 50
Cytomegalovirus (CMV) Infections
Mycobacterium avium complex (MAC)
Over time CD4 count drops. Takes years for this to happen. Starting ART as soon as possible at any count in order to prevent decline and thus certain OI's.
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AIDS Defining Opportunistic Illnesses in US, HIV Outpatient Cohort Study, 1994-2007
Original Source Buchacz K AIDS 1010;24:1549-59 . Image from National HIV Curriculum available at hiv.uw.edu..
DHHS GuidelinesHIV.gov
Evidence Rating: DHHS Guidelines
DHHS. Adult and Adolescent Guidelines. Updated 11.21.19.
Why do we still see OIs?
Undiagnosed or late diagnosis of HIV
Known HIV infection with poor retention in care
Not on stable antiretroviral therapy (ART)
Opportunistic Infections
Can be first presentation of HIV
Cause morbidity and mortality
Often preventable
OI Prophylaxis
Antiretroviral therapy (ART)
Immune reconstitution inflammatory syndrome (IRIS)
Important things to note and consider:
IRIS: immune reconst. syndrome: occurs in 20% of patients, usually in first 2 months of starting ART. As body immune system recovers new or latent infections can develop/manifest as body is able to recognize and fight diseases.
Relation to ART: sometimes medications used to treat HIV can interact with treatment given for OI- be aware ex TB.
Prevent: with ART and ppx, also with avoiding certain risks= to be discussed
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OI Prophylaxis
Primary Prophylaxis
Prevention of first episode of disease
Risk is based on CD4 count
Secondary Prophylaxis
Prevention of relapse of disease after treatment
.
Not every OI needs primary prophylaxis, guidelines which do: when to start and stop after x# months.
Which infections need secondary prophylaxis.
Chronic maintenance therapy = secondary prophylaxis
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Primary Prophylaxis
OI
Indication
Preferred
Pneumocystis Pneumonia (PCP)
CD4 < 200
CD4 < 14%
If ART initiation has to be delayed, CD4 200, but < 250 and can't monitor every 3 mos
TMP-SMX 1 DS tab PO daily
TMP-SMX 1 SS tablet daily
Toxoplasma gondii Encephalitis
Toxoplasma IgG positive with CD4 < 100
TMP-SMX 1 DS PO daily
Mycobacterium avium Complex (MAC)
CD4 < 50
Not recommended for those who immediately start ART
Rule out active disease before starting
Azithromycin 1200 mg PO once weekly
Clarithromycin 500 mg PO BID
Azithromycin 600 mg PO twice weekly
DHHS. Adult and Adolescent Guidelines Table 1. Updated 11.21.19.
*Only slide with doses listed
Can consider prophylaxis for CD4 200-250
DD: double strength and SS = single strength:
Mention:TMP-SMX 1 DS PO three times weeklya (BI)
Note that Bactrim confers ppx for both PJP and toxo
Some OI we do not ppx for: CMV, thrush
Disseminated MAC when disease is ruled out new change to the guidelines no more MAC prophylaxis
Note that Bactrim confers ppx for both PJP and toxo
Some OI we do not ppx for: CMV, thrush
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When to Stop Primary Prophylaxis
OI
Indications for Discontinuing Primary Prophylaxis
Indication for Restarting Primary Prophylaxis
Pneumocystis Pneumonia (PCP)
CD4 increased from < 200 to > 200 for > 3 mos in response to ART
Can consider when CD4 count 100-200 if HIV RNA < limit of detection for 3-6 mos
CD4 < 100
CD4 100-200 and HIV RNA above detection limit of assay
Toxoplasma gondii encephalitis
CD4 > 200 for > 3 mos in response to ART
Consider when CD4 100-200 if HIV RNA < limit of detection for at least 3-6 mos
Mycobacterium avium Complex (MAC)
Initiation of effective ART
CD4 < 50, only if not on fully suppressive ART
DHHS. Adult and Adolescent Guidelines Table 4. Updated 11.21.19.
.Data on which to base specific recommendations are inadequate, but one approach would be to stop primary prophylaxis in patients with CD4 counts of 100 to 200 cells/mm3 if HIV plasma RNA levels remain below limits of detection for at least 3 to 6 months (BII). Clinical and individual evaluation is important I would stretch to 6 months if fluctuating
A combined analysis of 10 European cohorts found a low incidence of TE in patients with CD4 counts between 100 and 200 cells/mm3, who were receiving ART and had HIV RNA plasma viral loads <400 copies/mL, and who had stopped or never received TE prophylaxis, suggesting that primary TE prophylaxis can be safely discontinued in patients with CD4 counts 100 to 200 cells/mm3 and HIV plasma RNA levels below limits of detection with commercial assays.36 Similar observations have been made with regard to stopping primary or secondary prophylaxis for PCP.36-38 Data on which to base specific recommendations are inadequate, but one approach would be to stop primary prophylaxis in patients with CD4 counts of 100 to 200 cells/mm3 if HIV plasma RNA levels remain below limits of detection for at least 3 to 6 months (BII).36
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Secondary Prophylaxis
Disease
Preferred Drug
Stop
PCP
TMP/SMX
(AI)
CD4 > 200 for > 3 months (AII)
Toxoplasmosis
Pyrimethamine + Sulfadiazine + Leucovorin (AI)
or
TMP/SMX (BII)
Completed initial therapy and CD4 > 200 for > 6 months (BI)
MAC
Clarithromycin + Ethambutol (AI)
or
Azithromycin + Ethambutol (AII)
Completed > 12 months therapy, asymptomatic and CD4 > 100 for > 6 months (AII)
Restart for PJP/toxo if CD4 <200.
Can consider if CD4 count 100-200 cells/L and HIV RNA remain below limits of detection for at least 3-6 months (BII)
IF PJP diagnosed when CD4>200..ppx lifelong!
Clindamycin 600 mg PO q8h + (pyrimethamine 2550 mg + leucovorin 1025 mg) PO daily (BI); must add additional agent to prevent PCP (AII), or
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Case Scenario 1
Mr A is a 36 yo man admitted with fever, weight loss and productive cough for 1 month. Prior to admission, he received 2 courses of antibiotics from his PCP without improvement in his symptoms. Over the last week, he noted progressively worsening shortness of breath and now cannot walk 15 feet without stopping to catch his breath
Epidemiology: lives in Florida, no travel, no street drug use, has male sex partners only
CBC & CMP normal
LDH 800 mg/dL
Room air ABG pH 7.44 PaCO2 32 mm Hg, PaO2 62 mm Hg, HCO3 20 mEq/L
What do you think is going on? How will you make a diagnosis?
Pneumocystis Pneumonia (PCP)
Causative organisms: Pneumocystis jiroveci
Prior to effective use of ART and PCP prophylaxis, occurred in up to 80% of people with AIDS
Initially thought to be a protozoan, but DNA analysis demonstrated it is a fungus
Airborne
Species specific: PJP only affects humans
First reported by Chagas in 1909, but he thought it was a morphologic form of T cruzi
Thought to be a protozoan until late 1980s when DNA analysis showed it to be a fungus
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Diagnosis
Nondefinitive
Chest Xray
High resolution chest CT
Exercise pulse ox
Labs
Elevated LDH (> 500 mg/dl)
1,3-beta-D-glucan 80 pg/mL
Definitive detection of organism in resp secretions or tissue
Induced sputum
Bronchoscopy
Transbronchial or open lung biopsy
Detection of P jiroveci organisms in sample
Beta-D-glucan sensitivity is high (major component of P jiroveci cell wall) but specificity low as people with HIV are at risk for multiple other fungal pathogens
Detection in sample immunofluorescent stain, methenamine silver, Giemsa silver, and toluidine blue-O. PCR is highly sensitive but cannot distinguish acute infection from colonization
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Chest Imaging Suggestive of PCP
Rice KM. Global Radiology CME. October 21, 2015.
Available at https://www.globalradcme.com/single-post/2015/10/21/Pneumocystis-Pneumon...
National HIV Curriculum Available at hiv.uw.edu.
Should Mr. A Be Admitted?
Mild to Moderate PCP
PaO2 > 70 mm Hg
A-a gradient < than 35
If nontoxic appearing, can consider outpatient treatment
Moderate to Severe PCP
Room air PO2 < 70 mm Hg
A-a gradient 35
Must be admitted
A-a Gradient = PAO2 PaO2
Patients with pneumonia have a physical barrier within the alveoli, which limits the diffusion of oxygen into the capillaries.However, these patients can ventilate (unlike the patient with hypoventilation), which will result in a well-oxygenated respiratory tract (A) with poor diffusion of oxygen across the alveolar-capillary unit and thus lower oxygen levels in the arterial blood
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PCP: Treatment(mild-moderate disease)
Preferred Regimen (oral)
TMP-SMX (high dose) (AI)
Alternative Regimens (oral)
Dapsone + TMP (BI)
Primaquine + clindamycin (BI)
Atovaquone (BI)
Oral outpatient therapy effective in pts with mild-moderate disease
Test for G6PD prior to using dapsone or primaquine
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PCP: Treatment(moderate-severe)
Preferred Regimen (AI)
TMP-SMX (IV) + steroids
Steroids if PaO2 <70 mmHg at room air or Alveolar-arterial O2 gradient 35 mm Hg
Start ASAP and within 72 hours of PCP therapy
Alternative Regimens
Pentamidine (AI)
Primaquine + clindamycin (AI)
PCP: Treatment
After completion of 21 day treatment, start secondary prophylaxis
Patients with PCP can be slow to improve
Watch out for nonadherence or IRIS-may need prolonged treatment/re-admit
Consider this in patient with HIV and pneumothorax
Failure of TMP-SMX is rare, even in people who were taking it for PCP prophylaxis
Bactrim failure rare look for other diagnosis
In mild-moderate PCP, start ART within 2 weeks
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Should Mr. A be started on ART? When?
ART should be started within 2 weeks of diagnosis of PCP
Zolopa AR, et al. PloS One. 2009;4:35575.
Case scenario 2
Mr. B is a 44 year old man arrives in the emergency room complaining of a 5 day history of headaches and new onset seizures. He is post-ictal after a witnessed seizure but can tell you he has a history of HIV and hasn't taken medications nor seen a healthcare provider in 9 months. There are no prior records in the health system.
Exam T 36.7C (98.1F) HR 91 RR 16 BP 164/96
No nuchal rigidity, negative Kernig's and Brudzinski's signs
Exam otherwise unremarkable
Labs: CSF WBC 102 Lymph 82% Monos 9%
RBC 13; protein 40; glucose 63
Opening pressure: 38 cm H2O (> 25 cm H2O abnormal)
Cryptococcal Meningitis
Most common cause of meningitis in people with advanced HIV
Cryptococcus neoformans > Cryptococcus gattii
Hallmark is meningoencephalitis or subacute meningitis symptoms
Headache, fever, altered mental status
Classic meningitis symptoms in only 1/4 to 1/3 of patients
May see signs/symptoms of elevated CSF pressure
Approximately 25-30% of pts have a normal CSF profile
Needs admission: lumbar puncture, IV treatment
Prolonged treatment course (induction, consolidation, maintenance)
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Mr. B Follow-up
CSF cryptococcal antigen 1:1024
CSF culture: Cryptococcus neoformans
Therapeutic LPs done daily and eventually a VP shunt was placed due to persistently elevated CSF pressure
Keppra started for seizure prophylaxis
Cryptococcal Meningitis: Treatment
Induction therapy for 2+ weeks
Preferred: Amphotericin B + flucytosine (5FC)
Preferred: liposomal formulation of amphotericin but can use other formulations
Consolidation therapy for 8 weeks
Preferred: fluconazole 800mg
Chronic maintenance therapy
Preferred fluconazole 200mg
Cryptococcal MeningitisChronic Maintenance Therapy: Duration
Duration (BII):
Completed 1 year of maintenance therapy
Asymptomatic
CD4 count 100 for 3 months and suppressed HIV RNA in response to effective ART
Restart maintenance if patient's CD4 drops less than 100
Case Scenario 3
Mrs. C Presented to the emergency room in rural Florida with complaint of enlarging blind spots in her vision for the last week. She has a history of HIV ith loss to follow and poor compliance with ART
She was referred to ophthalmology and saw them one week later, but had complete vision loss by that time.
CMV Retinitis
Imagebank.asrs.org
CMV retinitis is a full-thickness necrotizing retinitis, and the characteristic ophthalmologic appearance is that of fluffy, yellow-white retinal lesions, with or without intraretinal hemorrhage, with little inflammation of the vitreous unless immune recovery with ART intervenes.1
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CMV (virus)
Double-stranded DNA virus
CMV retinitis is most common manifestation
Can affect any organ, disseminate-colitis/esophagitis, encephalitis/ventriculitis, or hepatitis
No primary prophylaxis recommended (AI)
CMV viremia can be detected by PCR, antigen assays or culture
Usually but not always present in end organ disease
Some patients can have viremia and no end organ disease
Presents first in one eye (floaters, visual field defects) and then may spread to the other
Needs admission: eye exam and treatment (oral vs IV/intravitreal)
floaters, scotomata, or peripheral visual field defects.
Peripheral retinitis may be asymptomatic or present with floaters, scotomata, or peripheral visual field defects.Lungs, CNS, eso/colitis
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CMV Retinitis: Treatment
Preferred Regimen (AI)
Intravitreal injections of ganciclovir or
foscarnet (AIII)
+
Valganciclovir (high dose) for 14-21
days, then lower dosing (AI)
can transition from IV to PO when able
Foscarnet/cidofovir other alternative
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CMV Retinitis: Secondary Prophylaxis
Preferred Regimen (AI)
Valganciclovir
Duration:
CMV treatment for at least 36 months, lesions are inactive, with CD4 count >100 cells/mm3 for 3 to 6 months in response to ART (AII)
Discontinue in consultation with an ophthalmologist
Case Scenario 4
Ms. D is a 33 year old woman, recently diagnosed with HIV after presenting with Toxoplasma infection (for which she is receiving treatment). Five weeks ago you met with her to enroll her in the Ryan White case management services and she started ART shortly after. Today she is here to discuss things further and you note that she is very confused and agitated.
Toxoplasma gondii Encephalitis
Protozoan
Disease almost always due to reactivation of latent cysts
Prior to availability of ART, 12-month incidence of toxoplasma encephalitis was 33% in those with seropositive for T gondii and not on prophylaxis
Rare if CD4 > 200 greatest risk if CD4 < 50
Toxoplasma: Brain CT
http://neuroradiologyteachingfiles.com/bfa.html
Typically multiple
contrast-enhancing lesions in
gray matter of cortex or basal
ganglia, but can have
single or no lesions
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Treatment 6 weeks
Preferred Regimen (AI)
Pyrimethamine + sulfadiazine + leucovorin
Note: if pyrimethamine is unavailable/there is a delay in obtaining it, TMP-SMX should be utilized in place of pyrimethamine-sulfadiazine (BI)
Alternative Regimen
numerous others exist
Treat for at least 6 weeks but may be longer depending on clinical/radiological symptoms
Dosing for pyrimethamine is weight based (< or > 60 Kg)
Alternative regimens: numerous- involve clinda, Bactrim, dapsone etc
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TreatmentChronic Maintenance
Preferred Regimen (AI)
Pyrimethamine + sulfadiazine + leucovorin
Duration:
completed initial therapy
asymptomatic
CD4 count > 200 for > 6 months (BI)
When to Start Antiretroviral Therapy in T gondii Encephalitis?
No data
Many would start ART within 2-3 weeks after diagnosis of T gondii encephalitis
Should you start anticonvulsant therapy?
Only if patient has a seizure
If indicated, continue through period of acute therapy
DHHS. Adult and Adolescent Guidelines. Updated 11.21.19.
Immune Reconstitution Inflammatory Syndrome: IRIS
Inflammatory disease in response to a specific opportunistic pathogen weeks to months after starting ART
Paradoxical IRIS: Exacerbation of partially or recently treated OI
Unmasking IRIS: Inflammatory response to a previously undiagnosed OI
Caused by enhanced/dysregulated immune response to antigens
Greatest risk when starting ART at a high viral load and CD4 < 50
Can be difficult to identify diagnosis of exclusion
Management: treat OI, continue ART, treat with anti-inflammatory if necessary (NSAIDS, steroids)
IRIS can manifest as: TB, MAC, cryptococcus, CMV retinitis
Immune response leads to overwhelming production of inflammatory mediators
IRIS: immune reconst. syndrome: occurs in 20% of patients, usually in first 2 months of starting ART. As body immune system recovers new or latent infections can develop/manifest as body is able to recognize and fight diseases.
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When Should ART Be Started?
Opportunistic Infection
When to start ARV's
PJP/PCP
Within 2 weeks (AI)
Cryptococcus meningitis
Between 2-10 weeks (BIII)
Toxoplasma encephalitis
Within 2-3 weeks can be up to 6 weeks (CIII)
CMV retinitis
Within 2 weeks (CIII)
Tuberculosis
Pulmonary disease and CD4 < 50 within 2 weeks after TB treatment started
If CD4 > 50 (no suspected meningitis) within 8 weeks of TB therapy start
Candidiasis
No delay
CNS Disease in HIV: Differential Diagnosis
Toxoplasma
Lymphoma
Cryptococcus
Progressive multifocal leukoencephalopathy (PML)
CMV
Aseptic meningitis
HIV associated dementia
PET and SPECT scans helpful in differentiating toxoplasmosis, PML and lymphoma
CNS Lymphoma linked with EBV CSF positive for EBV
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Mycobacterium avium Complex (MAC)
Ubiquitous in the environment
Typically seen in people with CD4 < 50
Usually disseminated, multi-organ infection, though can be localized
Typical symptoms: weight loss, fever, night sweats, fatigue, diarrhea and abdominal pain
Physical finding: hepatomegaly, splenomegaly, or lymphadenopathy
Lab abnormalities: anemia, elevated liver alkaline phosphatase
Diagnosis: clinical signs/symptoms + isolation of MAC from cultures of blood, lymph node, bone marrow or other normally sterile tissue or body fluids
MAC: Treatment
DHHS. Adult and Adolescent Guidelines. Updated 11.21.19.
Oral Candidiasis
Dxline.info
Candidiasis
Oropharyngeal (thrush), esophageal
Concern when CD4 < 200
Painless, creamy white, plaque-like lesions on tongue
Esophageal candidiasis: chest pain' or burning, pain on swallowing, nausea -> other differentials exist (CMV, HSV, aphthous ulcers)
No routine primary prophylaxis (AIII), typically no need for chronic suppressive therapy
retrosternal' pain
Chronic suppressive therapy typically not recommended unless has severe or frequent episodes
Lesions can be easily scraped off with a tongue depressor or other instrument. Less commonly, erythematous patches without white plaques can be seen on the anterior or posterior upper palate or diffusely on the tongue. Angular cheilosis also can be caused by Candida. Because a proportion of HIV-infected patients with oropharyngeal candidiasis also manifest esophageal involvement, clinicians should ascertain whether there are symptoms suggestive of esophageal disease in patients with oropharyngeal candidiasis
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Candidiasis
Oral
Preferred therapy fluconazole 100 mg PO daily
Duration of therapy 7-14 days
Esophageal candidiasis
Preferred therapy fluconazole 100 mg PO or IV daily or Itraconazole oral solution 200 mg PO daily
Duration of therapy 14-21 days
Other Oral Lesions
Kaposi's Sarcoma HHV8
Oral hairy leukoplakia - EBV
Syphilis
Bacterial Pneumonia in HIV
Incidence has decreased since availability of ART, but remains more common in people with HIV than those without
Recurrent pneumonia (2 or more episodes in 1 year) is an AIDS defining condition
Can occur at any stage of HIV disease and at any CD4 count
All people with HIV, should receive an annual influenza vaccine
Tuberculosis: #1 OI Worldwide
Recent transmission, reactivation
Annual risk of reactivation in people with untreated latent tuberculosis infection and HIV is 3-16%
Clinical presentation depends on degree of immunodeficiency
CD4 > 200 TB limited to lungs, upper lobe fibronodular infiltrates +/- cavitation, caseating granulomas
CD4 < 200 extra-pulmonary, lower/middle lobe, interstitial, military infiltrates, non-caseating granulomas
Tuberculosis
Test for latent TB PPD 5 mm is positive in person with HIV, rule out active disease
Interferon gamma release assay (IGRA) Quantiferon TB Gold Plus or T-Spot
Significant TB exposure? Treat for latent TB regardless of PPD or IGRA
Active TB? Look out for drug-drug interactions between TB treatment and ART
OIs: Exposures and Prevention
Sexual- hepatitis A, B and C, Syphilis , Chlamydia, Gonorrhea
IV drug abuse (IVDA)-Hep B, Hep C , Bacterial infections
Environment
Other individuals
Animals/Pets
Food and Water
Travel
important to know about exposure in order to reduce/minimize risk
Background
Environment: ubiquitous, pets/wild animals, hobbies, activities
Ubiquitous: Candida, MAC, PJP
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OIs and Adherence
Adherence to antiretroviral therapy and OI prophylaxis predicts clinical outcomes
Remind patients that OIs are preventable in most cases!
Do not presume patients are taking their prophylaxis
When asking about adherence to ART also ask about adherence to prophylactic medications
Summary
While OIs are less common than in the past, they still occur
Risk for OIs predicted by CD4 count
May see multiple OIs in the same patient
Keep a high index of suspicion for OIs in people with low adherence or known advanced HIV
OIs can be prevented by ART and prophylaxis as well as counseling to avoid risks (see OI guidelines)
Questions?
Thank You.