3Pathophysiology Depletion of CD-4 cells (T-helper) HIV binds Cell entrycell death
4CD4-deficiency Direct mechanisms Indirect mechanisms Accumulation of unintegrated viral DNAInterference with cellular RNA processingIntracellular gp 120-CD4 autofusion eventsLoss of plasma membrane integrity because of viral buddingElimination of HIV-infected cells by virus-specific immune responsesIndirect mechanisms Aberrant intracellular signaling eventsSyncytium formationAutoimmunitySuperantigenic stimulationInnocent bystander killing of viral antigen-coated cellsApoptosisInhibition of lymphopoiesis
5CD4 depletion syndromes HIV/AIDSidiopathic CD4+ T lymphocytopeniaIatrogenicCorticosteroidsImmunosuppresants
6Opportunistic 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
7Treatment Guidelines Treatment of Tuberculosis - June 20, 2003 2001 USPHS/IDSA Guidelines for the Prevention of Opportunistic Infections in Persons Infected with HIVTreatment of Tuberculosis - June 20, 2003
8Rating 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 ; 18(3):421.
9Quality 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.
10HIV and fever Disseminated MAC Disseminated histo bartonellosis CMV before HAART, most common cause of FUO in advanced AIDS.Disseminated histobartonellosisCMVcryptococcosis
11Mycobacterium avium-intracellulare complex (MAC) DisseminatedFUOFever, night sweats, weight loss, diarrheaAnemia, elevated alkaline phosphataseGIVisceralpulmonaryLocalized"immune reconstitution" illnessesbiopsies show a granulomatous responselymphadenitis (mesenteric, cervical, thoracic)can mimic Pott's disease with disease presenting in the spinePulmonary
13MACSourcesFoodWatersoilScreening not rec b/c no data for benefit, although predicts diseaseNo recs for avoidance
14MAC prophylaxis Primary CD4 < 50 until >100 3 mo. (AI) ClarithromycinAzithromycinRifabutin (not combo-EI)Exclude TBDI’sSecondary for 12 mo and until CD4 no sx and CD4 >100 6 mo (BCx neg)Macrolide + ethambutol, +/- rifabutinHigh dose clarithromycin asso. W/higher mortality (EI)Clofazimine too many ADR’s (DII)Restart at CD4 <50-100
15Drug Interactions Azithromycin not affected by c P450 Protease inhibitorsIncrease clarithromycin levelsSome contraindicated w/rifabutinNNRTIs (efavirenz)Induce clarithromycin metabolismSome contraindicated w/rifabutin
16Bartonella Treatment Manifestations B. henselae and B. quintana Bacillary angiomatosis (BQ)Lymphadenitis (BH)Hepatosplenic disease (BH)peliosis hepatisGIBrainneuropsychboneB. henselae and B. quintanaTreatmentErythromycinTetracycline deriv.
17Bartonellosis HIV-higher incidence Older cats less likely to transmit Control fleasNo rec for primary prophylaxisConsider long-term suppression (C-III)
18CMV Risk groups Test IgG if lower risk group % IgG positive MSM IDU Childcare exposureTest IgG if lower risk groupNot IDU/MSM% IgG positiveVaries by country
19CMV Manifestations pneumonitis FUO GI pancytopenia CNS Gastritis/GU DU RetinitisBlurred visionscotomatafield cutsEncephalitisTransverse myelitisRadiculitispneumonitisGIGastritis/GUDUcolitis
20CMV Diagnosis Treatment Serology-not helpful Valganciclovir Tissue histopathologyMolecular diagnosticsAntigenPCRTreatmentValganciclovirGanciclovir 5 mg/kg IV bid × daysFoscarnet 60 mg/kg IV q8h or 90 mg/kg IV q12h × daysCidofovir 5 mg/kg IV weekly × 2 then every other weekImplants
21CMV prophylaxis Primary Secondary Can consider if IgG (+) and CD4 <50Oral ganciclovir or valganciclovirRegular optho examsDiscuss symptomsNOT acyclovir/valacyclovirSecondaryIntraocular alone not sufficientValganciclovirConsider stopping when CD4> moContinue regular f/uCMV-neg or leukopoor irradiated blood if CMV (-)
22HIV and diarrhea Cryptosporidium Microsporidiosis Isospora Giardia bacterial enteric infectionsSalmonellaShigellacampylobacterListeriaCMVCdiff
23HIV and diarrheaCrampy abdominal pain, bloating, and nausea suggest small bowelCryptosporidiaMicrosporidiaIsosporaGiardiacyclospora)MAC.High-volume, watery diarrhea with weight loss and electrolyte disturbance is most characteristic of cryptosporidiosisbloody stools with abdominal cramping and fever ( invasive bacterial pathogen)Clostridium difficileCMV colitis
24HIV and diarrhea Stool studies Thorough history Medication review O&PTrichromeAFBImmunohistoCdiffThorough historyMedication reviewLow threshold for flex sigGiven the availability of effective treatment; more aggressive evaluation that often includes endoscopy has replaced the less invasive approach.TreatmentAntimotility agentsImodium, LomotilOpiumCalciumoctreotide
25Bacterial Enteric Infections Prevention Seek vet care for animals with diarrheaWASH HANDSTravel precautionsBottled beveragesAvoid fresh produceAvoid iceConsider prophylaxis or early empiric therapyCipro 500 qdBactrimAvoidReptiles, chicks and ducklingsRaw eggsRaw poultry, meat and seafoodUnpasteurized dairy products/juicesRaw seed sproutsSoft cheesesDeli counters unless can reheatRefrigerated meat spreads
26Cryptosporidiumcoccidian protozoan (I. belli, C. cayetanensis, and Toxoplasma gondii)5%-10% of diarrhea in immunocompetentAsymptomatic carriersmammalian hosts-cattle, horses, rabbits, guinea pigs, mice.transmission fecal-oral.Waterborne outbreaks due to contamination of drinking waterthick-walled, highly resistant oocystexcysts in stomachsporozoites infect enterocytes and persist at the apical pole of intestinal epithelial cells-microscopic appearance of extracellular, adherent parasite
27Cryptosporidiosis prevention biopsyfecal examinationModifed AFBImmunohisto stainsTreatmentAzithromycinParomomycinOctreotidenitazoxanideHAARTClarithromycin/rifabutin work, but no data.Counsel regarding exposure-avoid fecesdiapersyoung animals (screen BIII)waterboil water when suggested (AI)filters (CIII)oystersbottled (CIII)
28Microsporidiosisobserved initially in intestinal biopsy specimens in 1982No disease in normal hosts2 typesEnterocytozoon bieneusi, reproduces within enterocytesEncephalitozoon (Septata) intestinalis infects epithelial cells and stromal cells of the lamina propria and causes systemic infectionDiagnosisDifficult to see by light microscopy-order trichrome stainTreatmentAlbendazole (for intestinalis)Atovaquonemetronidazole.No recs for prevention
29Isospora no other known host endemic in Brazil, Colombia, Chile, and parts of equatorial Africa and southwest Asia.seen rarely in normalsfecal-oral route
30Isospora histologic sections shown better with Giemsa on histo Immunocompetentwatery diarrheausually clear the infection within about 2 weeks;may persistHIV-chronic high-volume watery diarrheaDetection in stool samples difficult, and concentration or flotation methods. AFB +histologic sectionsVillus atrophy, eosinophil infiltrates, and disorganization of the epitheliumshown better with Giemsa on histoCipro better than Bactrim
31Cyclospora first reported in the 1980s endemic in tropical countries and other areas w/poor standards of hygiene and water purificationseverity related to the degree of immunosuppressionRx Bactrim
32CyclosporaEpidemics attributed to contamination of water supplies, fruits, and vegetablessimilar to Cryptosporidium but larger (8 to 10 mum versus 4 to 5 mum) and AFB +fecal-oral routeintermittent watery diarrhea for 3 > mo.infect enterocytes and proliferate within a supranuclear parasitophorous vacuole.
37PCP Diagnosis Symptoms Sputum for DFA Sputum cytology Findings Incidious onsetSOB>coughpneumothoraxFindingsdiffuse infiltrates in a perihilar or bibasilar distribution and a reticular or reticulonodular patternNo effusionElevated LDHSX>>>CXRNormal in 26%DiagnosisSputum for DFASputum cytologyBAL for sameHistopathology/stains
38PCPTMP 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 tidrash, fever, gastrointestinal symptoms, hepatitis, hyperkalemia, leukopenia, and hemolytic anemiaSteroid (pO2 < 70 or A-a gradient > 35)TMP-dapsoneClinda/primaquineAtovaquoneTrimetrexate/folinic acidIv Pentamnausea, infusion-related hypotension, hypoglycemia, hypocalcemia, renal failure, and pancreatitis
39PCP prophylaxis CD4<200 or history of oral thrush (AII) CD4%<14 or other OI (BII)Bactrim (AI)DS daily (toxo, bacterial pathogens)SS dailyDS TIW (BII)rechallenge if rash (desens) - 70% tolerate
41PCP prophylaxis Stop when CD4>200 for 3 mo. Restart if CD4<200 Stop secondary prophylaxis if CD4>200 unless PCP occurred at higher CD4Children of HIV mothers need prophylaxisChildren with PCP can not stop secondary prophylaxis.
42Histoplasmosis THE MOST common endemic mycosis Pulmonary, mucosal, disseminated or CNSRespiratory cultureBlood cultureBone marrow biopsyUrine AgSome cross reactionMore sensitive in dissem disease, esp HIVRx ampho, itraMississippi valley and Ohio valley + worldwideNormal hosts usually asympto or mild URI-no rx
44Histoplasmosis Prevention Routine skin testing not predictiveAvoidCreating soil/old building dustCleaning chicken coopsDisturbing bird roostsExploring cavesSecondary prophylaxisItraconazoleNo data-no rec for stoppingPrimary ProphylaxisNo proven survival benefitConsider in high risk and CD4<100
45Typical CAP Increased mortality with Pneumococcal Increased incidence of PseudomonasBactrim and macrolide prophylaxis prevent resp infections, but not rec solely for this reasonMaintain normal granulocyte count & IgGPreventionPneumovaxBII rec if CD4>200No data for CD4<200Repeat in 5 yearsRepeat when CD4 >200
46Tuberculosis Low threshold of suspicion Lower CD4=atypical presentationHigher mortalityTuberculin skin testing (TST) negative in 40% of patients with disease4-drug therapy initiallyDrug interactions major issue
49Tuberculosis New guidelines Emphasize DOT and provider responsibility Louis Pasteur once said, "The microbe is nothing...the terrain everything"Reculture at 2 mo of trxExtend if still + and cavitary diseaseINH--rifapentine once weekly continuation phase (Regimens 1c and 2b) is contraindicatedCD4+ cell counts <100/µl should receive daily or three times weekly treatment“paradoxical” flares occurAssociated w/HAARTEffusions, infiltrates, enlargement of CNS lesions, nodes, feverSteroids used
54Tuberculosis prevention PPD on diagnosis of HIV (5mm)if positive treatINH/B6 9 months (AII)rifampin 4 months (BIII)rif/PZA for 2 monthshepatic toxicityrifabutin can be sub’d (less data)Close contacts should be treated if HIV+if exposed to MDR TB needs expert advice and PHBCG contraindicatedVague guidelines for repeating PPDyearly if “high risk”repeat when CD4>200
55Coccidiocomycosis Growth is enhanced by bat and rodent droppings. Exposure is heaviest in the late summer and fallAcute pulm, chronic pulm, dissem, CNSmore severe in immunosuppressed individuals, African Americans, and Filipinos2/3 of immunosuppressed have disseminated diseaseAvoid disturbing native soilDiagnose by serology or biopsyBlood cultures not usually positiveSkin test not predictiveOften refractory to treatementSecondary prophylaxis lifelong, too little data for stopping (>100)
56Med Clin North Am - 01-Nov-2001; 85(6): 1461-91,
59HHV-8 Agent of Kaposi’s sarcoma Vertical transmission occurs No screening availableAntivirals may have some effectMay be accelerated if infected after HIVAdvise about preventionManifestationsCutaneousMucosalVisceralGIPulmonaryother
60Human papillomavirus Manifestations: Genital epithelial cancer Condyloma acuminataPlantar wartsFacialPeriungualGenital epithelial cancerTwice yearly screening, then annual in womenFollow NCI guidelinesScreening for men being developed
61Herpes HSV VZV Very common (>90% of MSM sero+) Prior frequent ADI, occurs at CDDermatomal, ocular, disseminatedNo effective secondary prevention recsAvoid exposureVaccinate relativesVZIG if exposed and negativeHSVVery common (>90% of MSM sero+)Severe, erosive disease, proctitisSome need chronic suppression (acyclovir/famcyclovir)Resistance occurs and cross-res w/ganciclovir.
62Candida Infections Responds quickly to therapy ManifestationsOral thrushEsophageal candidiasisCandidal dermatitisvulvovaginalTreatmentfluconazoleClotrimazoleNystatinItraconazoleAmphotericin (po or iv)Responds quickly to therapyPrimary prophylaxis not recSecondary is optional, prefer early empiric rxAzole resistance is an issue
63HIV and headache Cryptococcus-meningitis Toxoplasmosis-enhancing PML lymphomaHIVCMV (perivent)EBVnonenhancing
64Cryptococcus Diagnosis Treatment Meningitis Pulmonary disease Headachesubtle cognitive effects.Occaasional meningeal signs and focal neurologic findingsnonspecific presentation is the normPulmonary diseaseDisseminated diseaseFUOAdenopathySkin nodulesOrgan involvementDiagnosisCSF Ag sens=100%Need opening pressureTreatmentAmpho + 5FC (GI, hem toxicity)fluconazole
65Cryptococcal meningitis ICP management>250 mm H2 O was seen in 119 out of 221 patientshigher titers of cryptococcal antigenmore severe clinical manifestationsheadache, meningismus, papilledema, hearing loss, and pathologic reflexesshortened long-term survivalDesired OP < 200 mm H2 O or 50% of the initial pressureDaily lumbar punctures until the pressure is stableLumbar drainVentriculoperitoneal shuntingCorticosteroids are not recommended
66Cryptococcus Prevention Primary prophylaxis effective but generally not recSecondary until CD4> mo. and no sx (only CIII rec)Fluconazole (AI)Restart at <
67ToxoplasmosisToxoplasmosis 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 diagnosticToxo IgG + & no prophylaxis: Empiric RxClinical response is usually seen within 7 days (and often sooner), andradiographic response in 14 days.
68Toxoplasmosis Encephalitis sensorimotor deficits, seizure, confusion, ataxia.Fever, headache common.Multiple ring-enhancing lesionsAlmost always due to reactivation
69Toxoplasma TreatmentPyrimethamine mg then mg/d + folinic acid 10 mg/d + sulfadiazine 4-8 g/d for at least 6 weeksOr sub clinda, azithro, clarithro or atovaquoneSteroids if mass effect
70Toxoplasma prophylaxis Screen for IgG (BIII)if negative, aggressively counsel regarding avoidance of cat litter, raw meat (165 deg)wash, wear gloves when gardeningwash vegetableskeep cats indoors, avoid raw meat foodsgetting rid of or testing the cat is an EIII offense!CD4 <100 if seropositive only
71Toxoplasma 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)
72Toxoplasma primary prophylaxis Stop primary px when CD4 > 200 for 3 monthsstop secondaryrestart when CD4 drops <100 again
73Toxoplasma secondary prophylaxis After initial therapy completedPyrimethamine plus sulfadiazinepyrimethamine plus clinda (not for PCP)stop when CD4>200 for 6 months, no symptoms and initial therapy completedrestart if drop below 200
75What’s new? Drug interactions Immunization guidelines HHV-8 transmissionemphasized HCV screening
76ReferencesOpportunistic infections in HIV disease: down but not out. Sax PE - Infect Dis Clin North Am - 01-JUN-2001; 15(2):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, 2000Infectious diarrhea in human immunodeficiency virus. Cohen J - Gastroenterol Clin North Am - 01-SEP-2001; 30(3):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, 1996State-of-the-art review of pulmonary fungal infections. Seminars in Respiratory Infections. Volume 17 • Number 2 • June 2002