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

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

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

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

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 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

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 1994; 18(3):421.

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.

HIV and fever Disseminated MAC Disseminated histo bartonellosis CMV 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 Pulmonary

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

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

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

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

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.

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 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

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

CMV Diagnosis Treatment Serology-not helpful Valganciclovir Tissue histopathology Molecular diagnostics Antigen PCR Treatment Valganciclovir Ganciclovir 5 mg/kg IV bid × 14-21 days Foscarnet 60 mg/kg IV q8h or 90 mg/kg IV q12h × 14-21 days Cidofovir 5 mg/kg IV weekly × 2 then every other week Implants

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>100-150 6mo 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 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

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 cells-microscopic appearance of extracellular, adherent parasite

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)

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

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 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

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

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 CD4 HHV-8 Coccidiodomycosis

PCP

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

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

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

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

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.

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

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 CD4<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 & IgG Prevention Pneumovax BII rec if CD4>200 No data for CD4<200 Repeat in 5 years Repeat when CD4 >200

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

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

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

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)

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 CD4 < 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: 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

Herpes HSV VZV Very common (>90% of MSM sero+) Prior frequent ADI, occurs at CD4 200-500 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.

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

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

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

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

Cryptococcus Prevention Primary prophylaxis effective but generally not rec Secondary until CD4>100-200 6 mo. and no sx (only CIII rec) Fluconazole (AI) Restart at <100-200

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.

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

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

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

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 px when CD4 > 200 for 3 months stop secondary restart when CD4 drops <100 again

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

What’s new?

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

References Opportunistic infections in HIV disease: down but not out. Sax PE - Infect Dis Clin North Am - 01-JUN-2001; 15(2): 433-55 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): 637-64 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