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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 1 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. 2 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 3 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 4 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 5 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 6 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. 9 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 14 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 15 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 16 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 17 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 18 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 20 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 21 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 23 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 24 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 26 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) 29 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 34 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 35 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 36 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 40 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 41 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. 44 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 46 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 50 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 56 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.