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

Guidelines for Prevention and Treatment of Opportunistic Infections in HIVInfected Adults and Adolescents Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America Prepared by Jonathan E. Kaplan, MD 1 Constance Benson, MD 2 King K. Holmes, MD, Ph. D 3 John T. Brooks, MD 1 Alice Pau, Pharm. D 4 Henry Masur, MD 4 1 CDC, Atlanta, Georgia 2 University of California San Diego, California 3 University of Washington, Seattle, Washington 4 National Institutes of Health, Bethesda, Maryland

However… Remains a leading cause of morbidity and death in HIV patients because… 1) many patients are unaware of their HIV infection and seek medical care when an OI becomes the initial indicator of their disease; 2) certain patients are aware of their HIV infection, but do not take ART because of psychosocial or economic factors; and 3) certain patients are prescribed ART, but fail to attain adequate virologic and immunologic response because of factors related to adherence, pharmacokinetics, or unexplained biologic factors

Furthermore… The relation between OIs and HIV infection is bidirectional. – HIV leads to immunosuppression that allows opportunistic pathogens to cause disease in HIVinfected persons. – OIs and other coinfections that might be common in HIV-infected persons, such as sexually transmitted infections, can also have adverse effects on the natural history of HIV infection i. e increase viral load and therefore disease progression and transmission. – chemoprophylaxis and vaccination directly prevent pathogen-specific morbidity and mortality, but they might also contribute to reduced rate of progression of HIV disease.

Major changes in guidelines additional emphasis on the importance of ART for prevention and treatment of OIs, especially those for which specific chemoprophylaxis and treatment do not exist information on diagnosis and management of immune reconstitution inflammatory syndromes (IRIS) information on interferon-gamma release assays (IGRAs) for the detection of latent Mycobacterium tuberculosis infection updated information on drug interactions affecting use of rifamycin drugs for prevention and treatment of tuberculosis (TB); 5) addition of a section on hepatitis B virus (HBV) infection; and 6) addition of a section on malaria to the OIs of geographic interest.

Rating Strength of the Recommendation A Both strong evidence for efficacy and substantial clinical benefit support recommendation for use. Should always be offered. D Moderate evidence for lack of efficacy or for adverse outcome supports a recommendation against use. Should generally not 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. E Good evidence for lack of efficacy or for adverse outcome supports a recommendation against use. Should never 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. 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.

ART therapy in OI Benefits of ART have been demonstrated for cryptosporidiosis, PML, microsporidiosis, KS and other relatively untreatable OIs – Recommend begin ART (AIII) one recently completed randomized clinical trial has demonstrated a clinical and survival benefit of starting ART early, within the first 2 weeks, of initiation of treatment for an acute OI, excluding TB However, institution of ART during an OI can result in an exuberant immune response (IRIS) drug/drug interaction can also be difficult

ART in acute OI Main point: In cases of cryptosporidiosis, microsporidiosis, PML, KS, PCP, and invasive bacterial infections, the early benefits of ART outweigh increased risk related to these other factors and ART should be started as soon as possible

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 – 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 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 CD 4 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 B. henselae and B. quintana Manifestations – Bacillary angiomatosis (BQ) – Lymphadenitis (BH) – Hepatosplenic disease (BH) peliosis hepatis – GI – Brain neuropsych – bone 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 (nls) Microsporidiosis Isospora Giardia (nls) Cyclospora (nls) 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. thick-walled, highly resistant oocyst Waterborne outbreaks due to contamination of drinking water 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 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. 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 – Insidious onset – SOB>cough – Pneumothorax Before HAART, 70 -90% of AIDS pts got PCP, and mort was 20 -40% Findings – diffuse infiltrates in a perihilar or bibasilar distribution and a reticular or reticulonodular pattern – No effusion – Elevated LDH – SX>>>CXR Normal in 26% – Poor air movement Microbiology – P. jiroveci infects human – P. carinii infects rodents – 2/3 of kids are infected by 2 -4 yo – Fungus with protozoal properties Diagnosis (preferred) – Expectorated sputum much less sensitive – Sputum for DFA – Sputum cytology – BAL for same – Histopathology/stains Isolation controversial-some rec private room.

PCP treatment 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 (AI) rash, fever, gastrointestinal symptoms, hepatitis, hyperkalemia, leukopenia, and hemolytic anemia – Steroid (p. O 2 < 70 or A-a gradient > 35) – Mortality remains 50% in those requiring ICU or mech ventilation – TMP-dapsone – Clinda/primaquine – Atovaquone – Trimetrexate/folinic acid – Iv Pentam xtoxicity

PCP treatment complications methemoglobinemia and hemolysis with dapsone or primaquine (especially in those with G 6 PD deficiency) rash and fever with dapsone azotemia, pancreatitis, hypo- or hyperglycemia, leukopenia, electrolyte abnormalities, and cardiac dysrhythmia with pentamidine anemia, rash, fever, and diarrhea with primaquine and clindamycin headache, nausea, diarrhea, rash, and transaminase elevations with atovaquone IRIS Treatment failure

PCP prophylaxis CD 4<200 or history of oral thrush (AII) CD 4%<14 or other OI (BII) consider Bactrim (AI) – DS daily (toxo, bacterial pathogens) – SS daily – DS TIW (BII) – rechallenge if rash (desens) - 70% tolerate, can use gradual dose increase

PCP prophylaxis Dapsone + pyrimethamine/ leucovorin 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. (AI) 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.

Typical CAP Pulmonary Complications of HIV Infection Study – incidence 3. 9– 7. 3 episodes per 100 person-years – pre. HAART Increased mortality Most common Pneumococcal and H. flu Increased incidence of Pseudomonas and Staph Any age or CD 4 Treatment – Similar to non HIV but no macrolide alone – Be cautious about quinolone if TB suspected – IRIS has not been described

Typical CAP Diagnosis – c/w PCP, localized findings on exam – Lower threshold for testing b/c broad diff – BCx higher yield Prevention – Maintain normal granulocyte count & Ig. G – Bactrim and macrolide prophylaxis prevent resp infections, but not rec solely for this reason – Stop smoking, excess alcohol or drug use – Flu vaccine (not live) – Pneumovax BII rec if CD 4>200 No data for CD 4<200 (less data) Repeat in 5 years (even less data) Repeat when CD 4 >200

Tuberculosis Low threshold of suspicion Lower CD 4=atypical presentation Higher mortality – Per WHO cause of death in 12% of AIDS cases Tuberculin skin testing (TST) negative in 40% of patients with disease 1/3 of cases are primary in HIV 4 -drug therapy initially Drug interactions major issue Associated w/IRIS

TB-atypical presentation In advanced AIDS CXR different – Lower lobe, middle lobe, interstitial, and miliary infiltrates common – Cavitation less common – Marked mediastinal LAD – Normal CXR can be smear positive! Extrapulmonary more common – LAD, pleuritis, pericarditis, meningitis. – Sepsis-like syndrome Histopath may not show granulomas

Tuberculosis prevention PPD for all new diagnoses of HIV – Positive is >/= 5 IGRA can be used (but decreasing sens w/CD 4) Retest when immune reconstitution All latent TB in HIV gets treated, as do all close contacts w/HIV. – INH/B 6 9 months (AII) – rifampin 4 months (BIII) – rif/PZA for 2 months hepatic toxicity-no longer recommended – rifabutin can be sub’d (less data) Consider annual if continued risk – – – Employment Homeless Foreign travel

Tuberculosis-treatment 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 – Everyone gets 2 months 4 drugs, then 4 months 2 drugs at least – 3 extra months if cavitary and positive cx CNS disease gets 9 -12 months CD 4+ cell counts <100/µl should receive daily or three times weekly treatment “paradoxical” flares occur i. e IRIS – Associated w/HAART – Effusions, infiltrates, enlargement of CNS lesions, nodes, fever – Steroids used

Histoplasmosis THE MOST common endemic mycosis CD 4 <150 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 – At least a yr

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 (AII) – ACTG sudy reported success stopping if ART x 6 mo, >1 yr rx, neg BCx, histo ag <2, CD 4 >150 – Resume if fall <150 Primary Prophylaxis – No proven survival benefit – Consider in high risk and CD 4<100

Coccidiocomycosis Growth is enhanced by bat and rodent droppings. Exposure is heaviest in the late summer and fall Acute pulm, chronic pulm, dissem, CNS Southwestern United States and parts of Central and South America more severe in immunosuppressed individuals, African Americans, and Filipinos 2/3 of immunosuppressed have disseminated disease

Coccidiocomycosis Avoid disturbing native soil Diagnose by serology or biopsy (spherules) Blood cultures not usually positive Skin test not predictive Treatement – Amphotericin or azole – Often refractory to treatment Primary px in endemic areas if positive serology and low CD 4 Secondary prophylaxis can be stopped after 12 months of rx if CD 4 >250 and on HAART, and if focal PNA. Can’t stop if CNS or disseminated. High relapse rate (AII)

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 (HHV 8) Vertical transmission occurs No screening available HAART has enormous 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. – Prior frequent ADI, 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 when CSF cx neg, 2 wks, and improvement clinically

Forehead ulcer. This is in an HIVinfected host with Cryptococcus neoformans seen in histopathology. Cryptococcal nodule. This was a previously healthy, asymptomatic patient with a right lung nodule. Cytospin CSF preparation of host with cryptococcal meningitis. This shows an encapsulated yeast surrounded by a mixed inflammatory reaction.

Cryptococcal meningitis Intracranial pressure 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, mannitol and Diamox are not recommended

Cryptococcus Prevention Primary prophylaxis effective but generally not rec Secondary until CD 4 >200 6 mo. and no sx (BII) – Fluconazole (AI) (itra inferior) – Restart at <200

Toxoplasmosis Seroprevalence 15% in the United States and 50%--75% in certain European countries pre. ART, 1/3 of pts w/advanced AIDS got toxo within 12 months Usually CD 4 <50, rare for <200

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

Toxoplasmosis diagnosis 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 but insensitive 2. Toxo Ig. G + & no prophylaxis: Empiric Rx • Clinical response is usually seen within 7 days (and often sooner) • radiographic response in 14 days.

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 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 For CD 4<100 and seropositive Trim/sulfa DS qd (AII) dapsone/pyrimethamine plus leucovorin(BI) atovaquone (CIII) dapsone, macrolides, pyrimethamine don’t work (DII) Aerosolized pentam definitely doesn’t work (EII)

Toxoplasma primary prophylaxis Stop primary px when CD 4 > 200 for 3 months stop secondary when >200 6 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 in hospital – M avium complex (MAC) – no data – S pneumoniae and H influenzae – not practical – Candidiasis – not practical – Cryptococcosis – not practical

Review-when to stop prophylaxis

Other 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 State-of-the-art review of pulmonary fungal infections. Seminars in Respiratory Infections. Volume 17 • Number 2 • June 2002