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HIV II Update on Opportunistic Infections Prevention and Treatment.

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Presentation on theme: "HIV II Update on Opportunistic Infections Prevention and Treatment."— Presentation transcript:

1 HIV II Update on Opportunistic Infections Prevention and Treatment


3 Pathophysiology zDepletion of CD-4 cells (T-helper) zHIV binds zCell entry zcell death

4 CD4-deficiency zDirect mechanisms yAccumulation of unintegrated viral DNA yInterference with cellular RNA processing yIntracellular gp 120-CD4 autofusion events yLoss of plasma membrane integrity because of viral budding yElimination of HIV-infected cells by virus-specific immune responses z Indirect mechanisms yAberrant intracellular signaling events ySyncytium formation yAutoimmunity ySuperantigenic stimulation yInnocent bystander killing of viral antigen-coated cells yApoptosis yInhibition of lymphopoiesis

5 CD4 depletion syndromes zHIV/AIDS zidiopathic CD4 + T lymphocytopenia zIatrogenic yCorticosteroids yImmunosuppresants

6 Opportunistic infections zFor 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

7 Treatment Guidelines z2001 USPHS/IDSA Guidelines for the Prevention of Opportunistic Infections in Persons Infected with HIV zTreatment of Tuberculosis - June 20, 2003

8 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.

9 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.

10 HIV and fever zDisseminated MAC ybefore HAART, most common cause of FUO in advanced AIDS. zDisseminated histo zbartonellosis zCMV zcryptococcosis

11 Mycobacterium avium- intracellulare complex (MAC) zDisseminated yFUO xFever, night sweats, weight loss, diarrhea xAnemia, elevated alkaline phosphatase yGI yVisceral ypulmonary z Localized"immune reconstitution" illnesses ybiopsies show a granulomatous response ylymphadenitis (mesenteric, cervical, thoracic) ycan mimic Pott's disease with disease presenting in the spine yPulmonary

12 MAC zFindings yAdenopathy yElevated alk phos yanemia zDiagnosis yBlood culture yTissue culture yHistopathology z Treatment yMacrolide + ethambutol + rifabutin yAmikacin yciprofloxacin

13 MAC zSources yFood yWater ysoil zScreening not rec b/c no data for benefit, although predicts disease zNo recs for avoidance

14 MAC prophylaxis zPrimary CD mo. (AI) yClarithromycin yAzithromycin yRifabutin (not combo-EI) xExclude TB xDI’s zSecondary for 12 mo and until CD4 no sx and CD4 >100 6 mo (BCx neg) yMacrolide + ethambutol, +/- rifabutin yHigh dose clarithromycin asso. W/higher mortality (EI) yClofazimine too many ADR’s (DII) zRestart at CD4 <50-100

15 Drug Interactions zAzithromycin not affected by c P450 zProtease inhibitors yIncrease clarithromycin levels ySome contraindicated w/rifabutin z NNRTIs (efavirenz) yInduce clarithromycin metabolism ySome contraindicated w/rifabutin

16 Bartonella zManifestations yBacillary angiomatosis (BQ) yLymphadenitis (BH) yHepatosplenic disease (BH) xpeliosis hepatis yGI yBrain xneuropsych ybone zB. henselae and B. quintana z Treatment yErythromycin yTetracycline deriv.

17 Bartonellosis zHIV-higher incidence zOlder cats less likely to transmit zControl fleas zNo rec for primary prophylaxis zConsider long-term suppression (C-III)

18 CMV zRisk groups yMSM yIDU yChildcare exposure zTest IgG if lower risk group xNot IDU/MSM z% IgG positive yVaries by country

19 CMV zManifestations yFUO ypancytopenia yCNS xRetinitis Blurred vision scotomata field cuts xEncephalitis xTransverse myelitis xRadiculitis ypneumonitis yGI xGastritis/GU xDU xcolitis

20 CMV zDiagnosis ySerology-not helpful yTissue histopathology yMolecular diagnostics xAntigen xPCR z Treatment yValganciclovir yGanciclovir 5 mg/kg IV bid × days yFoscarnet 60 mg/kg IV q8h or 90 mg/kg IV q12h × days yCidofovir 5 mg/kg IV weekly × 2 then every other week yImplants

21 CMV prophylaxis zPrimary yCan consider if IgG (+) and CD4 <50 yOral ganciclovir or valganciclovir yRegular optho exams yDiscuss symptoms yNOT acyclovir/valacyclovir z Secondary yIntraocular alone not sufficient yValganciclovir yConsider stopping when CD4> mo yContinue regular f/u z CMV-neg or leukopoor irradiated blood if CMV (-)

22 HIV and diarrhea zCryptosporidium zMicrosporidiosis zIsospora zGiardia z bacterial enteric infections ySalmonella yShigella ycampylobacter yListeria z CMV z Cdiff

23 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

24 HIV and diarrhea zStool studies yO&P yTrichrome yAFB yImmunohisto yCdiff zThorough history zMedication review zLow threshold for flex sig z Given the availability of effective treatment; more aggressive evaluation that often includes endoscopy has replaced the less invasive approach. z Treatment yAntimotility agents xImodium, Lomotil xOpium yCalcium yoctreotide

25 Bacterial Enteric Infections Prevention zSeek vet care for animals with diarrhea zWASH HANDS zTravel precautions yBottled beverages yAvoid fresh produce yAvoid ice yConsider prophylaxis or early empiric therapy xCipro 500 qd xBactrim z Avoid yReptiles, chicks and ducklings yRaw eggs yRaw poultry, meat and seafood yUnpasteurized dairy products/juices yRaw seed sprouts ySoft cheeses yDeli counters unless can reheat yRefrigerated meat spreads

26 Cryptosporidium zcoccidian protozoan (I. belli, C. cayetanensis, and Toxoplasma gondii) z5%-10% of diarrhea in immunocompetent zAsymptomatic carriers zmammalian hosts-cattle, horses, rabbits, guinea pigs, mice. ztransmission fecal-oral. z Waterborne outbreaks due to contamination of drinking water z thick-walled, highly resistant oocyst z excysts in stomach z sporozoites infect enterocytes and persist at the apical pole of intestinal epithelial cells- microscopic appearance of extracellular, adherent parasite

27 Cryptosporidiosis prevention zbiopsy zfecal examination yModifed AFB yImmunohisto stains zTreatment yAzithromycin yParomomycin yOctreotide ynitazoxanide yHAART z Clarithromycin/rifabutin work, but no data. z Counsel regarding exposure-avoid feces ydiapers yyoung animals (screen BIII) ywater xboil water when suggested (AI) xfilters (CIII) xoysters xbottled (CIII)

28 Microsporidiosis zobserved initially in intestinal biopsy specimens in 1982 zNo disease in normal hosts z2 types yEnterocytozoon bieneusi, reproduces within enterocytes yEncephalitozoon (Septata) intestinalis infects epithelial cells and stromal cells of the lamina propria and causes systemic infection z Diagnosis yDifficult to see by light microscopy-order trichrome stain z Treatment yAlbendazole (for intestinalis) yAtovaquone ymetronidazole. z No recs for prevention

29 Isospora zno other known host zendemic in Brazil, Colombia, Chile, and parts of equatorial Africa and southwest Asia. zseen rarely in normals zfecal-oral route

30 Isospora zImmunocompetent ywatery diarrhea yusually clear the infection within about 2 weeks; ymay persist zHIV-chronic high-volume watery diarrhea zDetection in stool samples difficult, and concentration or flotation methods. AFB + z histologic sections yVillus atrophy, eosinophil infiltrates, and disorganization of the epithelium z shown better with Giemsa on histo z Cipro better than Bactrim

31 Cyclospora zfirst reported in the 1980s zendemic in tropical countries and other areas w/poor standards of hygiene and water purification zseverity related to the degree of immunosuppression zRx Bactrim

32 Cyclospora zEpidemics attributed to contamination of water supplies, fruits, and vegetables zsimilar to Cryptosporidium but larger (8 to 10 mum versus 4 to 5 mum) and AFB + zfecal-oral route zintermittent watery diarrhea for 3 > mo. zinfect enterocytes and proliferate within a supranuclear parasitophorous vacuole.


34 HIV and pneumonia zPCP zhistoplasmosis zcryptococcosis zrhodococcus zCMV z Pneumococcus y100-fold risk z Nontypable H. flu z Pseudomonas y40-fold risk yLowest CD4 z HHV-8 z Coccidiodomycosis


36 PCP

37 zSymptoms yIncidious onset ySOB>cough ypneumothorax zFindings ydiffuse infiltrates in a perihilar or bibasilar distribution and a reticular or reticulonodular pattern yNo effusion yElevated LDH ySX>>>CXR xNormal in 26% z Diagnosis ySputum for DFA ySputum cytology yBAL for same yHistopathology/stains

38 PCP zTMP 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 ySteroid (pO2 35) yTMP-dapsone yClinda/primaquine yAtovaquone yTrimetrexate/folinic acid yIv Pentam xnausea, infusion-related hypotension, hypoglycemia, hypocalcemia, renal failure, and pancreatitis

39 PCP prophylaxis zCD4<200 or history of oral thrush (AII) zCD4%<14 or other OI (BII) z Bactrim (AI) yDS daily (toxo, bacterial pathogens) ySS daily yDS TIW (BII) yrechallenge if rash (desens) - 70% tolerate

40 PCP prophylaxis zDapsone zDapsone + pyrimethamine/leucov orin zaerosolized pentam (Respirgard II)- pregnancy 1st term zatovaquone z Other aerosolized Pentam z parenteral pentam z oral pyrimethamine/ sulfadoxine z oral clinda/primaquine z trimetrexate All BIAll CIII

41 PCP prophylaxis zStop when CD4>200 for 3 mo. zRestart if CD4<200 zStop secondary prophylaxis if CD4>200 unless PCP occurred at higher CD4 z Children of HIV mothers need prophylaxis z Children with PCP can not stop secondary prophylaxis.

42 Histoplasmosis zMississippi valley and Ohio valley + worldwide zNormal hosts usually asympto or mild URI-no rx z THE MOST common endemic mycosis z Pulmonary, mucosal, disseminated or CNS z Respiratory culture z Blood culture z Bone marrow biopsy z Urine Ag ySome cross reaction yMore sensitive in dissem disease, esp HIV z Rx ampho, itra

43 Clin Chest Med - 01-DEC-1996; 17(4):

44 Histoplasmosis Prevention zRoutine skin testing not predictive zAvoid yCreating soil/old building dust yCleaning chicken coops yDisturbing bird roosts yExploring caves z Secondary prophylaxis yItraconazole yNo data-no rec for stopping z Primary Prophylaxis yNo proven survival benefit yConsider in high risk and CD4<100

45 Typical CAP zIncreased mortality with Pneumococcal zIncreased incidence of Pseudomonas zBactrim and macrolide prophylaxis prevent resp infections, but not rec solely for this reason z Maintain normal granulocyte count & IgG z Prevention yPneumovax xBII rec if CD4>200 xNo data for CD4<200 xRepeat in 5 years xRepeat when CD4 >200

46 Tuberculosis zLow threshold of suspicion zLower CD4=atypical presentation zHigher mortality zTuberculin skin testing (TST) negative in 40% of patients with disease z 4-drug therapy initially z Drug interactions major issue



49 Tuberculosis zNew guidelines yEmphasize DOT and provider responsibility xLouis Pasteur once said, "The microbe is nothing...the terrain everything" yReculture at 2 mo of trx xExtend if still + and cavitary disease z INH--rifapentine once weekly continuation phase (Regimens 1c and 2b) is contraindicated z CD4 + cell counts <100/µl should receive daily or three times weekly treatment z “paradoxical” flares occur yAssociated w/HAART yEffusions, infiltrates, enlargement of CNS lesions, nodes, fever ySteroids used





54 Tuberculosis prevention zPPD on diagnosis of HIV (5mm) zif positive treat yINH/B6 9 months (AII) yrifampin 4 months (BIII) yrif/PZA for 2 months xhepatic toxicity yrifabutin can be sub’d (less data) z Close contacts should be treated if HIV+ z if exposed to MDR TB needs expert advice and PH z BCG contraindicated z Vague guidelines for repeating PPD yyearly if “high risk” yrepeat when CD4>200

55 Coccidiocomycosis zGrowth is enhanced by bat and rodent droppings. zExposure is heaviest in the late summer and fall zAcute pulm, chronic pulm, dissem, CNS zmore severe in immunosuppressed individuals, African Americans, and Filipinos z2/3 of immunosuppressed have disseminated disease z Avoid disturbing native soil z Diagnose by serology or biopsy z Blood cultures not usually positive z Skin test not predictive z Often refractory to treatement z Secondary prophylaxis lifelong, too little data for stopping (>100)

56 Med Clin North Am - 01-Nov-2001; 85(6): ,

57 HIV and rash zMolluscum zHHV-8 (KS) zHPV zVZV zHSV zcryptococcus zBartonella zSyphilis z Candida z Seborrheic dermatitis z Folliculitis yEosinophilic ybacterial z Psoriasis z Onchomycosis z Prurigo nodularis z scabies

58 Molluscum contagiosum zPapular eruption yPearly yumbilicated zPoxvirus zUsually CD4 < 200 zRx liquid nitrogen

59 HHV-8 zAgent of Kaposi’s sarcoma zVertical transmission occurs zNo screening available zAntivirals may have some effect zMay be accelerated if infected after HIV yAdvise about prevention z Manifestations yCutaneous yMucosal yVisceral xGI xPulmonary xother

60 Human papillomavirus zManifestations: yCondyloma acuminata yPlantar warts yFacial yPeriungual yGenital epithelial cancer xTwice yearly screening, then annual in women xFollow NCI guidelines xScreening for men being developed

61 Herpes zHSV yVery common (>90% of MSM sero+) ySevere, erosive disease, proctitis ySome need chronic suppression (acyclovir/famcyclovir) yResistance occurs and cross-res w/ganciclovir. z VZV yPrior frequent ADI, occurs at CD yDermatomal, ocular, disseminated yNo effective secondary prevention recs yAvoid exposure yVaccinate relatives yVZIG if exposed and negative

62 Candida Infections zManifestations yOral thrush yEsophageal candidiasis yCandidal dermatitis yvulvovaginal zTreatment yfluconazole yClotrimazole yNystatin yItraconazole yAmphotericin (po or iv) z Responds quickly to therapy z Primary prophylaxis not rec z Secondary is optional, prefer early empiric rx z Azole resistance is an issue

63 HIV and headache zCryptococcus-meningitis zToxoplasmosis-enhancing zPML zlymphoma zHIV zCMV (perivent) zEBV nonenhancing

64 Cryptococcus zMeningitis yHeadache ysubtle cognitive effects. yOccaasional meningeal signs and focal neurologic findings ynonspecific presentation is the norm zPulmonary disease zDisseminated disease yFUO yAdenopathy ySkin nodules yOrgan involvement z Diagnosis yCSF Ag sens=100% yNeed opening pressure z Treatment yAmpho + 5FC (GI, hem toxicity) yfluconazole

65 Cryptococcal meningitis zICP management y>250 mm H 2 O was seen in 119 out of 221 patients xhigher titers of cryptococcal antigen xmore severe clinical manifestations headache, meningismus, papilledema, hearing loss, and pathologic reflexes shortened long-term survival yDesired OP < 200 mm H 2 O or 50% of the initial pressure yDaily lumbar punctures until the pressure is stable yLumbar drain yVentriculoperitoneal shunting yCorticosteroids are not recommended

66 Cryptococcus Prevention zPrimary prophylaxis effective but generally not rec zSecondary until CD4> mo. and no sx (only CIII rec) yFluconazole (AI) yRestart at <

67 1.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 2.Toxo IgG + & no prophylaxis: Empiric Rx Clinical response is usually seen within 7 days (and often sooner), and radiographic response in 14 days. Toxoplasmosis

68 zEncephalitis ysensorimotor deficits, seizure, confusion, ataxia. yFever, headache common. yMultiple ring-enhancing lesions yAlmost always due to reactivation

69 Toxoplasma Treatment zPyrimethamine mg then mg/d + folinic acid 10 mg/d + sulfadiazine 4-8 g/d for at least 6 weeks zOr sub clinda, azithro, clarithro or atovaquone zSteroids if mass effect

70 Toxoplasma prophylaxis zScreen for IgG (BIII) yif negative, aggressively counsel regarding avoidance of cat litter, raw meat (165 deg) ywash, wear gloves when gardening ywash vegetables ykeep cats indoors, avoid raw meat foods ygetting rid of or testing the cat is an EIII offense! zCD4 <100 if seropositive only

71 Toxoplasma primary prophylaxis zTrim/sulfa DS qd (AII) zdapsone/pyrimethamine (BI) zatovaquone (CIII) zdapsone, macrolides, pyrimethamine don’t work (DII) zAerosolized pentam definitely doesn’t work (EII)

72 Toxoplasma primary prophylaxis zStop primary px when CD4 > 200 for 3 months zstop secondary zrestart when CD4 drops <100 again

73 Toxoplasma secondary prophylaxis zAfter initial therapy completed zPyrimethamine plus sulfadiazine zpyrimethamine plus clinda (not for PCP) zstop when CD4>200 for 6 months, no symptoms and initial therapy completed zrestart if drop below 200

74 What’s new?

75 zDrug interactions zImmunization guidelines zHHV-8 transmission zemphasized HCV screening

76 References zOpportunistic infections in HIV disease: down but not out. Sax PE - Infect Dis Clin North Am - 01-JUN-2001; 15(2): zGraybill 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 zInfectious diarrhea in human immunodeficiency virus. Cohen J - Gastroenterol Clin North Am - 01-SEP-2001; 30(3): zAMERICAN 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 zState-of-the-art review of pulmonary fungal infections. Seminars in Respiratory Infections. Volume 17 Number 2 June 2002

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