HIV II Update on Opportunistic Infections Prevention and

HIV II Update on Opportunistic Infections Prevention and Treatment

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

CD 4 -deficiency Direct mechanisms – Accumulation of unintegrated viral DNA – Interference with cellular RNA processing – Intracellular gp 120 -CD 4 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

CD 4 depletion syndromes HIV/AIDS idiopathic CD 4+ T lymphocytopenia Iatrogenic – Corticosteroids – Immunosuppressants

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 • Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents: http: //www. cdc. gov/mmwr/pdf/rr/rr 5804. pdf

Major Changes in Guidelines Increased emphasis on importance of ART More information about IRIS Information about using IGRAs for latent TB diagnosis More drug interactions data Addition of section on Hepatitis B treatment Addition of section on malaria.

ART therapy in OI Benefits of ART have been demonstrated for cryptosporidiosis, PML, microsporidiosis, KS and other relatively untreatable OIs – Recommend begin ART (AIII) – KS essentially goes away However, institution of ART during an OI can result in an exuberant immune response Drug/drug interaction can also be difficult

ART therapy in OI TB, MAC, PCP, crytococcal infection – Highest association with IRIS – Wait for clinical response to OI rx before starting ART (CIII) When OI develops within first 12 weeks of ART initiation, begin OI rx and do not stop ART (AIII) A RCT demonstrated a clinical and survival benefit of starting ART withint the first 2 wks of initiation of rx for OI, except for TB Zolopa A, Andersen J, Komarow L, et al. Immediate versus deferred ART in the setting of acute AIDS-related OI: final results of a randomized strategy trial, ACTG A 5164. 15 th CROI; 2008; Boston, MA. Abstract 142.

Management of acute OI after starting ART First group: within 12 wks, may be unmasked, therefore don’t represent failure of ART >/= 12 wks with high CD 4 (IRIS vs failure of ART? ) >/= 12 wks after ART with virologic failure

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

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 or other bones/joints – Pulmonary

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

MAC Sources – Food – Water – soil Stool screening not rec b/c no data for benefit, although predicts disease No recs for avoidance

MAC prophylaxis Primary CD 4 < 50 until >100 3 mo. (AI) – Clarithromycin – Azithromycin – Rifabutin (not combo-EI) Exclude TB DI’s Secondary for 12 mo and until no sx and CD 4 >100 6 mo (BCx neg) – Macrolide + ethambutol, +/- rifabutin – High dose clarithromycin asso. W/higher mortality (EI) – Clofazimine too many ADR’s (DII) Restart at CD 4 <50 -100

Drug Interactions Azithromycin not affected by c P 450 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 B. henselae and B. quintana Treatment – Erythromycin – Tetracycline deriv.

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 Ig. G if lower risk group Not IDU/MSM % Ig. G positive – Varies by country

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

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 q 8 h or 90 mg/kg IV q 12 h × 14 -21 days – Cidofovir 5 mg/kg IV weekly × 2 then every other week – Implants

CMV prophylaxis Primary – Can consider if Ig. G (+) and CD 4 <50 – Oral ganciclovir or valganciclovir – Regular optho exams – Discuss symptoms – NOT acyclovir/valacyclovir Secondary – Intraocular alone not sufficient – Valganciclovir – Consider stopping when CD 4>100 -150 6 mo – 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 Treatment – – – Azithromycin Paromomycin (Octreotide-now DII) nitazoxanide HAART Clarithromycin/rifabutin work, but no data. Counsel regarding exposure-avoid feces – – – Private room Diapers Animals with diarrhea young animals (screen BIII) water boil water when suggested (AI) filters (CIII) oysters bottled (CIII)

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. – nitazoxanide 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 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

Cyclospora first reported in the 1980 s 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.

HIV and pneumonia PCP histoplasmosis cryptococcosis rhodococcus CMV Pneumococcus – 100 -fold risk Nontypable H. flu Pseudomonas – 40 -fold risk – Lowest CD 4 HHV-8 Coccidiodomycosis

PCP

PCP Symptoms – 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% – Extrapulmonary disease

PCP Microbiology – – P. jiroveci infects human P. carinii infects rodents Fungus with protozoal properties Primary infection usually early childhood Diagnosis (preferred) – – – Expectorated sputum much less sensitive Sputum for DFA Sputum cytology BAL for same Histopathology/stains Mortality 60% in patients requiring mechanical vent

PCP TMP 15 mg/kg/d + SMX 75 mg/kg/d po or IV × 21 days in 34 divided doses; for outpatient, 2 DS tablets po tid (AI) rash, fever, gastrointestinal symptoms, hepatitis, hyperkalemia, leukopenia, and hemolytic anemia Steroid (p. O 2 < 70 or A-a gradient > 35)-21 d taper (AI) Alternatives – – – TMP-dapsone (BI) Clinda/primaquine (BI) Atovaquone (less effective in mild-mod) (BI) Trimetrexate/folinic acid (keep fol for 3 d after last dose)-(AI) Iv Pentam (BI) nausea, infusion-related hypotension, hypoglycemia, hypocalcemia, renal failure, and pancreatitis

PCP prophylaxis CD 4<200 or history of oral thrush (AII) CD 4%<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 + pyrimethamine/leucov orin aerosolized pentam (Respirgard II)pregnancy 1 st term atovaquone All BI Other aerosolized Pentam parenteral pentam oral pyrimethamine/ sulfadoxine oral clinda/primaquine trimetrexate All CIII

PCP prophylaxis Stop when CD 4>200 for 3 mo. Restart if CD 4<200 Stop secondary prophylaxis if CD 4>200 unless PCP occurred at higher CD 4 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 CD 4<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 & Ig. G Prevention – PCV-13 followed by polysaccharide vaccine

Tuberculosis Low threshold of suspicion Lower CD 4=atypical presentation Higher mortality Tuberculin skin testing (TST) negative in 40% of patients with disease 4 -drug therapy initially Drug interactions major issue

Tuberculosis prevention PPD for all new diagnoses Consider annual if continued risk – Employment – Homeless – Foreign travel

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 1 c and 2 b) is contraindicated CD 4+ 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

“Treatment of tuberculosis benefits both the community as a whole and the individual patient, thus and public health program or private provider undertaking to treat a patient with tuberculosis is assuming a public health function that includes not only prescribing an appropriate regimen, but also insuring adherence to the regimen until treatment is completed. ”

Tuberculosis prevention PPD on diagnosis of HIV (5 mm) IGRA can also be used if positive treat – INH/B 6 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 CD 4>200

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)

Coccidiomycosis Treatment – Amphotericin +/- an azole – Fluconazole for CNS disease 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 CD 4 < 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. – occurs at CD 4 200 -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 Pulmonary disease Disseminated disease – FUO – Adenopathy – Skin nodules – Organ involvement Diagnosis – CSF Ag sens=100% – Need opening pressure Treatment – Ampho + 5 FC (GI, hem toxicity) – fluconazole

Cryptococcal meningitis ICP management – >250 mm H 2 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 H 2 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 CD 4>100 -200 6 mo. and no sx (only CIII rec) – Fluconazole (AI) – Restart at <100 -200

Toxoplasmosis Encephalitis – sensorimotor deficits, seizure, confusion, ataxia. – Fever, headache common. – Rare if CD 4>200 – Multiple ring-enhancing lesions – Almost always due to reactivation of latent tissue cysts

Toxoplasmosis Diagnosis – Ig. G seropositivity with appropriate lesions on MRI – PCR is only 50% sensitive – Biopsy is gold standard

Toxoplasma Treatment Pyrimethamine 100 -200 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 Anticonvulsants only if seizure activity (DIII) Strongly consider biopsy if treatment failure

Toxoplasma prophylaxis Screen for Ig. G (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! CD 4 <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 when CD 4 > 200 for 3 months restart when CD 4 drops <100 again

Toxoplasma secondary prophylaxis After initial therapy completed Pyrimethamine plus sulfadiazine pyrimethamine plus clinda (not for PCP) stop when CD 4>200 for 6 months, no symptoms and initial therapy completed restart if drop below 200

Prevention of Exposure Currently, there are no recommendations for preventing exposure to: – P jiroveci pneumonia (PCP) – no data to support isolation – M avium complex (MAC) – no data – S pneumoniae and H influenzae – not practical – Candidiasis – not practical – Cryptococcosis – not practical

Summary of stopping prophylaxis