Opportunistic Infections and Immune Reconstitution Inflammatory Syndrome

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1 Disclosures Opportunistic Infections and Immune Reconstitution Inflammatory Syndrome I have received grant funding from the National Institutes of Health and the Gilead Research Scholars Program in HIV. Catherine Koss, MD Assistant Professor Division of HIV, Infectious Diseases, and Global Medicine December 7, 2018 Objectives Diagnose and manage common opportunistic infections (OIs) in HIV Know the indications and preferred regimens for primary prophylaxis for OIs Understand the features and management of immune reconstitution inflammatory syndrome (IRIS) Understand the data regarding when to start ART in the setting of an acute OI CD4 cell count CD4 count correlates with risk of specific OIs in untreated HIV disease TB VZV/Zoster Pneumococcal/bacterial PNA Lymphoma Kaposi sarcoma Pneumocystis PNA Toxoplasmosis MAC Histoplasmosis Cryptococcosis CMV PML Cryptopsoridiosis Primary CNS Candidal esophagitis lymphoma > <50 CD4 count strata Adapted from Bartlett JG et al. Medical Management of HIV, [footer text here]

2 With potent ART, incidence of OIs continues to decline N = 63,541 U.S. patients in NA ACCORD, We still see OIs among: 1) Patients newly diagnosed with HIV who present with an OI (late HIV diagnoses) 2) Patients who are aware of their HIV status but face barriers to taking ART PCP 3) Patients for whom ART fails to achieve adequate immunologic/virologic response Candidal esophagitis CD4 <200 or OI at HIV diagnosis United States, 2016 MAC 40% 30% 27% 33% 36% 20% 17% 10% 9% 0% Age, years Buchacz K et al. JID CDC HIV Surveillance Supplemental Report 2018; 23(4) Resources for OI management Case 1 44 y/o M with HIV CD4 94 cells/mm 3 not on ART or prophylaxis 1 month of progressive dyspnea, non productive cough, fevers, night sweats, and weight loss Ward 86 Management Recommendations ward86 index Exam: Afebrile, 90% RA Diffuse crackles bilaterally and mild wheezing Labs: WBC 8.3 LDH 386, BDG>500 ABG: 7.44/35/59 on room air 2 [footer text here]

3 CT Chest Which empiric therapy would you start? 1. Ceftriaxone + doxycycline 2. TMP SMX + prednisone 3. Ceftriaxone + doxycycline + TMP SMX + prednisone 4. RIPE 5. Ganciclovir Case 1 continued Pneumocystis pneumonia Started on empiric CTX/doxycycline + TMP SMX/prednisone Could not obtain induced sputum BAL performed for microbiologic confirmation: - Bacterial culture: oral flora - AFB smear and culture: negative - PCP positive CTX + doxycycline stopped TMP SMX + prednisone continued PCP = Pneumocystis pneumonia Caused by P. jiroveci - ubiquitous fungus - P. carinii now refers to the organism that infects rodents 90% of cases occur at CD4<200 cells/mm 3 - Most cases with CD4 <100 Subacute presentation of nonproductive cough, progressive dyspnea, fever, chest discomfort Hypoxemia Normal lung exam or dry crackles DHHS OI Guidelines [footer text here]

4 PCP: Imaging See Dec 6 talk by Dr. Laurence Huang PCP: Laboratory diagnostics CXR pattern: - Classic: bilateral, reticular interstitial infiltrates - Lobar disease is uncommon - Pleural effusions, cavitation, intrathoracic adenopathy are rare - May be normal If normal CXR high resolution CT for ground glass - High negative predictive value Cystic disease increased risk of spontaneous pneumothorax PTX should prompt high suspicion for PCP Elevated LDH: Common, non specific Plasma β D glucan - Sensitivity 92%, specificity 65% for PCP using a cutoff of 80 pg/ml 1 Median level in PCP was 408 pg/ml vs. 37 pg/ml without PCP - (1 3) β D glucan is a component of the cell wall of most fungi (including P jirovecii) Other causes of positive BDG: candidiasis, histoplasmosis, cryptococcus Diagnosis requires microbiologic confirmation. No culture system for P. jirovecii. Stains differ depending on lab; sensitivity depends on method, experience of lab Sensitivity of stained respiratory secretions - Induced (not expectorated) sputum: <50 90% - BAL: % - Organisms persist in specimens for days weeks after rx Do not delay empiric therapy DHHS OI Guidelines Sax P et al. CID Treatment of PCP Why use steroids in PCP? With steroids Disease severity Moderate to severe PaO2 <70 A a grad 35 Preference Preferred Regimen (21 days then start secondary ppx) TMP + SMX (weight based) Adjust dose for renal function IV PO after clinical improvement Steroids within 72 hours Prednisone 40 mg BID x 5 days Prednisone 40 mg daily x 5 days Prednisone 20 mg daily x 11 days Potential toxicities Adverse effects are common Rash, fever, leukopenia, thrombocytopenia, azotemia, hepatitis, hyperkalemia Try to treat through reactions if possible Desensitization protocols available for patients with allergy STOP and do not re challenge if pt has Stevens Johnson syndrome or toxic epidermal necrolysis Initiation of PCP therapy often causes pulmonary function in the first 3 5 days This may be due to inflammation Cutoff: RA PaO 2 <70 mm Hg or A a gradient>35 mm Hg Without steroids Mild Preferred TMP + SMX (weight based) PaO2 70 A a grad <35 A a grad <30 Survival A a grad >30 DHHS OI Guidelines NIH UC Expert Panel for Corticosteroids as Adjunctive Therapy for PCP. NEJM Montaner et al. Ann Int Med Brenner et al. Am Rev Respir Dis el Sadr and Simberkoff. Am Rev Respir Dis [footer text here]

5 PCP: Treatment failure If patient not improving after 3 days, is this treatment failure? - Generally no; early worsening at 3 5 days is common - Wait at least 4 8 days for a clinical response before switching therapy for clinical failure Evaluate for concurrent infections as a cause for clinical failure consider repeat bronch Disease severity Moderate to severe PaO2 <70 A a grad 35 Preference Preferred Alternative #1 (rx failure/ toxicity) Alternative #2 PCP: Treatment Regimen (21 days then start secondary ppx) TMP + SMX (weight based) Adjust dose for renal function IV PO after clinical improvement Steroids within 72 hours Prednisone 40 mg BID x 5 days Prednisone 40 mg daily x 5 days Prednisone 20 mg daily x 11 days Clindamycin + primaquine + steroids Check G6PD Pentamidine IV + steroids Historically preferred. Higher mortality in retrospective studies. We avoid. Potential toxicities Adverse effects are common Rash, fever, leukopenia, thrombocytopenia, azotemia, hepatitis, hyperkalemia Try to treat through reactions if possible Desensitization protocols available for patients with allergy STOP and do not re challenge if pt has Stevens Johnson syndrome or toxic epidermal necrolysis Anemia, rash, fever, diarrhea Irreversible renal and pancreatic islet cell toxicities, arrhythmias, hypoglycemia, hypotension Mild Preferred TMP + SMX PaO2 70 A a grad <35 Alternative Clindamycin + primaquine. Check G6PD Dapsone + TMP. Check G6PD Atovaquone BID with food Anemia, rash, fever, diarrhea Rash, fever HA, nausea, diarrhea, rash, LFTs DHHS OI Guidelines DHHS OI Guidelines NIH UC Expert Panel for Corticosteroids as Adjunctive Therapy for PCP, NEJM Case 2 Case 2 continued 40 yo M with HIV (CD4 420 and VL <40 on DTG + FTC/TAF 1.5 years ago), lost to follow up. Presents with several weeks of progressive symptoms: diffuse abdominal pain, fever, diarrhea (10x per day), and cachexia. CT shows bulky necrotic nodes in mediastinum and retroperitoneum. PMH: - HIV diagnosed 2 years ago, CD4 380, VL 80K Social History: - Immigrated to CA from Mexico 20 years ago - Marginally housed Labs: - Hgb 7, normal LFTs, Cr CD4 48 (6%), VL pending 5 [footer text here]

6 CT chest Numerous pulmonary nodules in UL and RML, largest 1.8 cm What is the most likely diagnosis? 1. Cytomegalovirus (CMV) 2. Mycobacterium tuberculosis (TB) 3. Mycobacterium avium complex (MAC) 4. Lymphoma Syndromic differential can help predict pathogens in patients with CD4<50 Case 2 continued Short DDx: AIDS + fever + wasting + lymphadenopathy Disseminated MAC Tuberculosis Disseminated fungal (Histo, Crypto) Lymphoma Short DDx: AIDS + pulmonary nodules Tuberculosis Fungal (Crypto, Coccidioidomycosis) Kaposi sarcoma Lymphoma Short DDx: AIDS + prolonged diarrhea Parasites (cryptosporidium, microsporidium) Bacterial (Salmonella, Shigella), mycobacterial (MAC; TB ileitis) Viral: CMV colitis Fungal: Histoplasmosis Other: HIV enteropathy, Malignancy: lymphoma, Kaposi sarcoma (HHV8) Stool cultures and O&P Giardia Ag positive Serum Cryptococcal Ag (CrAg) negative Urine Histoplasma Ag negative Sputum AFB smear x3 negative AFB blood cx drawn; started on empiric treatment for MAC Restarted ART: Dolutegravir + FTC/TAF 6 [footer text here]

7 When to suspect Mycobacterium Avium complex Clinical: Fever, weight loss, +/ diarrhea, +/ abd pain Laboratory: CD4 <50 Elevated alkaline phosphatase Anemia/pancytopenia due to bone marrow infiltration Diagnostics: AFB blood cultures (*draw prior to azithromycin) Sensitivity 91% for 1 AFB blood cultures Sensitivity 98% for 2 AFB blood cultures CT abdomen often reveals hepatosplenomegaly and intrabdominal lymphadenopathy May need tissue biopsy (e.g. lymph node) MAC Treatment: At least two drugs Drug 1: Macrolide Drug 2 +/ Drug 3 +/ Drug 4 Clarithromycin (more data) Or Azithromycin (better tolerated, fewer drug interactions) Ethambutol Rifabutin Moxifloxacin Levofloxacin Ciprofloxacin Consider a 3 rd drug if high burden of disease or pt not on ART Monitoring: Repeat AFB blood cx at 4 weeks Consider treatment failure if no improvement in sx still bacteremic after 4 weeks of rx Amikacin Streptomycin Duration: at least 1 year and CD4 >50 Benson and Ellner. CID Karakousis PC et al. Lancet Infect Dis DHHS OI Guidelines Ward 86 Management Recommendations, HIV InSite. Primary MAC prophylaxis: Evolving guidelines 369 patients with CD4 <50 on ART in HIV Outpatient Study (HOPS), incident MAC infections - 0 in patients with HIV RNA <1000 c/ml regardless of whether on ppx DHHS guidelines 2 recommend ppx until CD4 >100 (last updated 2013; update in progress) IAS USA guidelines 3 no longer recommend primary MAC ppx Our practice at Zuckerberg San Francisco General Hospital: 4 - If patient has signs/symptoms (fever, weight loss, LAD, HSM, diarrhea) of dmac Start empiric MAC treatment + ART Monotherapy for MAC high rate of macrolide resistance; MAC IRIS can be severe - If patient does not have signs/symptoms of dmac Start primary prophylaxis + ART Discontinue ppx when VL <1000 regardless of CD4 PCP OI Toxoplasma gondii MAC Prophylaxis of OIs: The basics Indications for primary ppx CD4<200 or CD4<14% CD4<100 and Toxo IgG+ CD4<50 and no evidence of dmac Regimen of choice and alternative regimens TMP SMX 1 DS daily TMP SMX 1 SS daily TMP SMX 1 DS 3x/wk Dapsone 1,2 Aerosolized pentamidine 2 Atovaquone with meal TMP SMX 1 DS daily TMP SMX 1 DS 3x/wk Dapsone + pyrimethamine + leucovorin 1 Atovaquone with meal Azithro 1200 mg weekly Azithro 600 mg 2x/wk Rifabutin 300 mg daily 3 When to stop primary ppx (in pts on ART) CD4>200 x >3 mo and VL ND OR CD4 >100 and VL ND x3 6 months CD4>200 x >3 mo and VL ND OR CD4 >100 and VL ND x3 6 months CD4>100 x >3 mo and VL ND 4 OR VL <1000 regardless of CD4 5 Considerations for secondary ppx/ chronic maintenance rx Start secondary ppx after completing PCP rx If pt has PCP at CD4>200 on ART, consider life long secondary ppx After initial Toxo rx, switch to chronic maintenance rx until CD4 >200 x >6 mo. (Pyrimethamine + sulfadiazine + leucovorin preferred) Continue treatment for dmac regimen for 12 mos and until CD4 >50 and no signs of dmac 1. Yangco BG et al. AIDS Pat Care STDs DHHS OI Guidelines Saag M et al. JAMA Ward 86 Management Recommendations, HIV InSite. 1. Check for G6PD deficiency. 2. Does NOT provide Toxoplasma ppx 3. Monitor for drug interactions, r/o active TB. 4. DHHS OI Guidelines Ward 86 Management Recommendations, HIV InSite. 7 [footer text here]

8 Back to case: Underwent colonoscopy and lung biopsy Colonoscopy Granulomatous inflammation with AFB Colonoscopy Cytopathic changes consistent with CMV Lung biopsy: Kaposi sarcoma Occam s razor does not apply consider multiple concurrent OIs Nucleomegaly and smudgy chromatin Stains for HHV8+ H&E: spindle cells 8 [footer text here]

9 AIDS related CMV end organ disease Usually occurs when CD4<50 - Reactivation of latent infection Case 2 continued Three weeks after re starting ART, the patient was readmitted with new fever to 39.4, worsening abdominal pain. CMV EOD (in order of frequency): Retinitis: - Diagnosed by dilated exam by experienced ophthalmologist GI: colitis, esophagitis - Tissue dx: visual or endoscopic evidence of erosion or ulcers with CMV inclusions on path Neuro: encephalitis, polyradiculitis, myelopathy - Clinical dx; CSF CMV DNA confirmatory Pneumonitis: very rare in AIDS, usually bystander in BAL and not cause of pulmonary disease Diagnostics CMV serology, serum PCR, and viral culture not helpful Patients with CMV GI or neurologic disease should have dilated eye exam Treatment Valganciclovir or ganciclovir Depends on clinical entity CT showed mild increase in size of mediastinal/intra abdominal lymph notes nodes and increased bowel wall enhancement. CD4 went from 46 > 85, and VL 200K > 18K. Labs are otherwise unchanged. DHHS OI Guidelines What is on your differential diagnosis? 1. Medication nonadherence 2. New OI 3. IRIS 4. Treatment failure 5. All of the above DDx: Worsening of OI after starting ART Immune reconstitution inflammatory syndrome (IRIS) Adverse med effect Treatment failure - Nonadherence - Resistance* - Poor absorption of medications New OI Malignancy Autoimmune condition * In dmac, susceptibility testing for clarithromycin (but no other drugs) correlated with clinical response 9 [footer text here]

10 What is Immune Reconstitution Inflammatory Syndrome (IRIS)? Paradoxical versus unmasking IRIS Syndrome of exaggerated immune response to antigens AFTER ART start - ~1 week to 3 months after ART start with decrease in VL +/ increase in CD4 - risk if starting ART at low CD4 (<50) or high VL - Little is known about pathogenesis Patient ON treatment for OI Start ART Paradoxical IRIS Usually due to infections but can also be due to malignancy (e.g. KS) Incidence and presentation vary by OI - ~30% of patients with dmac (can be severe) - PCP IRIS has been described, 2 but is rare Exaggerated immune response to persistent antigens of an OI that is being treated Patient NOT on treatment for OI Start ART Unmasking IRIS Exaggerated immune response to viable pathogens that were subclinical and not being treated 1. Müller M et al. Lancet Infect Dis Jagannathan P et al. AIDS IRIS: Management Step 1: Continue ART (except if patient has encephalitis) Step 2: Optimize or initiate treatment of the OI Step 3: Supportive and symptom directed therapy - Most cases resolve in several weeks of continuing ART and OI rx Step 4: Consider anti inflammatory therapies - NSAIDs for less severe symptoms - Corticosteroids most commonly used for moderate to severe disease Often start prednisone 1mg/kg and taper based on clinical response Best evidence for TB; we also use in MAC Consider in CMV immune recovery uveitis, severe CM IRIS Make sure no evidence of Kaposi sarcoma steroids can cause rapid, fatal worsening Case 2: Follow Up The patient was started on NSAIDS and symptoms resolved Steroids avoided due to KS Repeat AFB blood cultures negative Likely paradoxical IRIS Two months later, imaging showed improvement in abdominal LAD Marais et al. Curr HIV/AIDS Rep Ward 86 Management Recommendations, HIV InSite. 10 [footer text here]

11 Case 3 Studies at presentation 51 M with PMH of diverticulitis presents with - 1 month of progressive dyspnea on exertion, dry cough, fatigue - Sweats, fevers, 10 lb weight loss - Noticed a pimple on forehead that had ruptured and left open wound \ 13.0 / / 39.8 \ N 78%, L 16.6%, M 23% Rapid HIV Ag/Ab (+) Sputum AFB smear ( ) x 3 Serum CrAg (+) 1:32,768 Waiting for CD4 result? Normal absolute lymphocyte count has 96% predictive value for CD4 >100 cells/mm 3 Jacobson MA et al. AIDS What is your next management step? 1. Perform LP to evaluate for meningitis 2. Initiate fluconazole for cryptococcal pneumonia Cryptococcal meningitis can present without headache or AMS Order serum CrAg if CD4 <100 and any of the following: - Fever, headache, AMS, pneumonia Perform LP if newly positive serum CrAg (even if asymptomatic) Ward 86 Management Recommendations. HIV InSite. 11 [footer text here]

12 Case 3 continued CD4 = 39 LP: OP 28 cm, WBC 2 (N0, L93, M7), RBC 2, Glu 60, Prot 42 - CSF CrAg 1:128 - CSF cx C neoformans Induced sputum + BAL - C neoformans Skin bx cx - C neoformans Blood cx - C neoformans Most cases occur when CD4<100 Clinical: - Presents as subacute meningitis or meningoencephalitis - Can also see encephalopathic signs/sx due to elevated ICP Diagnosis: Cryptococcal meningitis - Serum and CSF CrAg are almost always positive - CSF studies: lymphocytic pleocytosis or no cells, mildly elevated protein, glucose normal to low, elevated OP Low CSF WBC portends a poorer prognosis - CSF culture is gold standard - CrAg used for diagnosis, NOT evaluating response to therapy need culture DHHS OI Guidelines 2018 Cryptococcal meningitis: Treatment Induction (at least 14 days): - Liposomal amphotericin B (AmBisome) 3 4 mg/kg/d plus - Flucytosine (5 FC) 100mg/kg/d in 4 divided doses Dose adjust in renal impairment If patient improving + repeat CSF cx negative Consolidation (8 weeks): - Fluconazole 400mg (6mg/kg) PO daily Chronic maintenance (at least 1 year): - Fluconazole 200mg PO daily for at least 1 year - AND CD4>100 and VL suppressed x3 months on ART Monitor for electrolyte abnormalities (hypokalemia) creatinine cytopenias Give IV fluids (normal saline) CM: Mainstay of management is control of elevated intracranial pressure Elevated ICP - can cause clinical deterioration even with microbiologic response - leading cause of death from CM in the first 2 wks after diagnosis Management: Measure OP at diagnosis If OP is elevated >20 cm H2O and pt has sx: - LP every hours to remove volume (~20 30cc) to bring the OP down to 20 cm H2O or by 50% - Aim for at least 2 days of stable pressures Consider lumbar drain if sx persist (refractory headache, N/V, confusion, clonus, papilledema) despite daily LPs Ventriculoperitoneal (VP) shunt should only be placed in exceedingly rare circumstances (cannot control ICP after 2 4 wks of maximal therapy) DHHS OI Guidelines IDSA Guidelines, CID DHHS OI Guidelines Ward 86 Management Recommendations, HIV Insite. 12 [footer text here]

13 When should you start ART? Starting ART during an acute OI 1. Now 2. After 2 weeks 3. After 6 weeks 4. After 10 weeks Advantages Sometimes ART is the best treatment for the OI - PML, cryptosporidiosis, microsporidiosis Prevention of a second OI Restore pathogen specific immunity (more rapid clearance of OI) Slow HIV progression Disadvantages Risk of IRIS - especially if occurs in CNS or eye When to start ART in cryptococcal meningitis? COAT Trial: 177 pts in Uganda + South Africa 282 patients with acute OI or serious bacterial infection - 63% PCP, 12% cryptococcus, excluded TB; median CD4 29 Randomized to: - Early ART = within 2 wks of starting therapy for OI (median 12 days,) - Deferred ART = after OI treatment complete (at 6 12 wks) (median 45 days) Lower risk of AIDS progression/death in early arm - 14% in early vs 24% in deferred arm; p= Few IRIS cases (6% in early vs 9% in deferred arm) Zolopa A et al. PLoS ONE 2009 CM Rx: Amphotericin + Fluconazole 800mg daily x 2weeks, then Fluc 800 until CSF sterile then Fluc 400 x 8wks Stopped early excess mortality Earlier ART (n=88) Deferred ART (n=89) Timing of ART start, median (IQR) 9 days (8 9) 36 days (34 38) Death by 6 months CSF WBC <5 cells/mm 3 45% HR 2.21 ( ) Boulware D et al. NEJM % ref Used fluconazole instead of flucytosine Repeat LPs may have been less available DHHS guidelines: wait 2 10 weeks p=0.03 p=0.008 CCM IRIS 16.2% 10.1% p= [footer text here]

14 When NOT to immediately start ART in the setting of an acute OI? Case 4 The Zuckerberg San Francisco General Hospital Experience Inflammatory CNS lesion - Brain edema, mass effect, or neurologic deficit - We recommend waiting at least 14 days from start of OI therapy. Limited data. Cryptococcal meningitis - We wait at least 14 days 37 y/o M with HIV CD4 28 off ART and prophylaxis presents with fever, altered mental status, and seizure CMV retinitis - We wait 14 days. Limited data. 1 TB meningitis - We wait 14 days. (To be discussed tomorrow by Sarah Puryear.) Ward 86 Management Recommendations, HIV InSite. 1. Orgeta Larrocea G et al. AIDS What is on your differential diagnosis? Selected differential diagnosis of focal neurologic disease in AIDS 1. CNS lymphoma 2. Toxoplasmosis 3. Pyogenic brain abscess 4. All of the above Short Differential Toxoplasma gondii Primary CNS lymphoma * PML: White matter only, no mass effect, non enhancing except in PML IRIS Bacterial Pyogenic abscess Nocardia Tuberculoma/NTM Syphilis Parasitic Toxoplasma gondii Trypanosoma cruzii (chagoma) Long Differential Fungal Cryptococcoma Histoplasma Aspergillus Viral Progressive multifocal leukoencephalopathy (JC Virus)* Malignancy Primary CNS lymphoma Metastases Skiest DJ. CID Chamie G et al. Semin Neurol [footer text here]

15 Toxoplasmic encephalitis: Epi and clinical Occurs at CD4<100 Transmission occurs by ingesting oocysts excreted in cat feces (litter/soil), undercooked meat (pork and lamb) or raw shellfish containing tissue cysts Disease almost exclusively due to reactivation of latent infection - Seroprevalence in the US is 3 30%; higher globally Subacute presentation over several weeks: - HA, fever, behavioral changes, confusion, hemiparesis, seizures, ataxia, CN palsies Toxoplasma can rarely cause disseminated disease - Pneumonitis (can mimic PCP), retinitis DHHS OI Guidelines Skiest DJ. CID Toxoplasmic encephalitis: Imaging and diagnosis Lesions can be single or multiple: - Classic: 2 ring enhancing lesions with surrounding edema - 27% 43% of patients have a single lesion - Rare: diffuse encephalitis with no focal lesions Serum Toxoplasma IgG: - If negative, virtually excludes infection - <3% 6% of patients with TE have negative IgG CSF studies: - Normal or mild increase in protein, lymphocytic pleocytosis, low glucose - Toxo CSF PCR: Sens ~50%, spec %. Does not r/o disease. - Also send CSF for EBV DNA, cytology, other studies as appropriate In practice: a clinical diagnosis based on low CD4, Toxo IgG+, imaging 1) Treat empirically 2) Repeat MRI in 2 weeks 3) If no improvement in exam/imaging, consider other diagnoses and brain biopsy Skiest DJ. CID Toxoplasmic encephalitis: Treatment Preference Regimen Potential toxicities First line pyrimethamine (weight based) + sulfadiazine (weight based) + leucovorin Duration: at least 6 weeks then chronic maintenance therapy: pyrimethamine + sulfadiazine + leucovorin (also provides PCP ppx) Alternative pyrimethamine (leucovorin) + clindamycin* (for clinical TMP/SMX alone** failure/toxicity) atovaquone + pyrimethamine (leucovorin) atovaquone + sulfadiazine atovaquone * Preferred. Does not provide PCP prophylaxis. Pyrimethamine: rash, nausea, and bone marrow suppression (can treat by increasing leucovorin dose) Sulfadiazine: rash, fever, leukopenia, hepatitis, nausea, vomiting, diarrhea, and crystalluria acute kidney injury (encourage hydration) ** If pyrimethamine unavailable or delay in obtaining, TMP/SMX should be used. Avoid steroids (if possible) if treating empirically because will also treat lymphoma Occurs usually at CD4<50 - Subacute presentation Imaging: Primary CNS Lymphoma - Lesions can be single or multifocal - Usually enhance homogenously, but can also be ring enhancing - Characteristic finding is lesion next to CSF (e.g. periventricular, meningeal, subependymal) CSF findings: - Mildly elevated protein and pleocytosis - EBV PCR: sensitivity >80%, specificity % For dosing, refer to DHHS OI Guidelines Skiest DJ. CID [footer text here]

16 Back to the case The patient was Toxo IgG+ and started on empiric therapy for Toxoplasmosis CSF EBV DNA and cytology negative He improved over the next 2 weeks and a biopsy was deferred Key points OI incidence declining; still important cause of morbidity/mortality CD4 count guides differential diagnosis in pts with untreated HIV Occam s razor does not apply consider multiple concurrent OIs OIs can be prevented with ART and primary and secondary ppx - Indication for ppx depends on CD4 cell count and viral suppression - New data on primary ppx for MAC Start ART as soon as possible except in specific situations: - Cryptococcal meningitis; TB meningitis (discussed by Sarah Puryear tomorrow) - CNS lesion with edema/mass effect, neurologic deficit; ocular OIs CMV retinitis Increased risk of IRIS with low CD4 - Evaluate for other etiologies of worsening, continue ART - Consider NSAIDs; steroids may be beneficial, minimize duration, avoid in KS Acknowledgements Diane Havlir Meg Newman Annie Luetkemeyer Monica Gandhi Mark Jacobson Carina Marquez Gabriel Chamie Jen Babik Vivek Jain 16 [footer text here]