A. Epidemiology [1]

1. HIV-1 and HIV-2 cause AIDS
   1. Nearly all HIV infection in USA due to HIV-1
   2. HIV-2 is closely related to simian immunodeficiency virus (SIV)
2. Likely Transmitted from Chimpanzies [2]
   1. Appears that three independent transmission events in early 20th century
   2. All 3 events involved bloodborne chimpanzee (likely SIVcpz virus) to human transmission
   3. The major event (between 1915 and 1941) lead to Group "M" (major) virus transmission
   4. Other Groups: Outlier "O" and non-major, non-outlier "N"
   5. Group O may have come from gorillas
   6. Earliest documented infection in humans (Group M) traced to blood sample from 1959
3. In USA, 700,000 to 900,000 persons are infected with HIV in 2000
   1. More than 200,000 of these are unaware that they are infected
   2. About 40,000 new cases of HIV infections annually in USA
   3. About 360,000 persons have AIDS in USA in 2001
   4. About 20,000 deaths per year in USA
4. Worldwide as of 2001
   1. About 37 million persons are infected with HIV
   2. About 5 million new HIV infections annually
   3. About 3 million deaths annually
5. Average lifespan (HIV+, HCV-) ~9 years in 2005 (Denmark Study) [44]
6. Risk Factors for Transmission
   1. Sexual transmission (homosexual and heterosexual) mainly with M tropic (R5) virus
   2. Increased risk of sexual transmission with anal intercourse (versus vaginal)
   3. Increased risk with contact with prostitutes and large number of sexual partners
   4. Male circumcision associated with 50-60% reduced risk of HIV transmission [50,51]
   5. Needle sharing by intravenous drug abusers (IVDA) is increasing source
   6. HIV is shed from genital herpes simplex virus (HSV) lesions in HIV-1 infected men
   7. Mother to child transmission risk ~25% without antiretroviral drug prophylaxis
   8. Prior to blood screening, Factor VIII concentrates were a major problem (before 1985)
7. Prevention
   1. Use of condoms is only clear method fore reducing sexual spread of HIV
   2. Spermicide with nonoxynol-9 does not reduce spread
   3. Treatment of urethritis in men reduces concentration of semen HIV-1
   4. IVDA - clean needles, avoid sharing needles, bleaching needles
   5. Immediate use of combination antiretroviral therapy (ART) after exposure
   6. Vaccines in development

B. HIV Structure

1. HIV Serotypes [2]
   1. There are 9 serotypes of HIV-1 Group M, and one of HIV-1 Groups O and N, now known
   2. The 9 serotypes of Group M are designated A through J (not including I)
   3. Groups A through D are most common
   4. In USA, HIV Group M, serotype B is the most subtype (or clade) of HIV
   5. No clear prognostic value of any particular subtype
   6. HIV-2 also occurs in USA and routine testing for that virus began in 1993
   7. Attenuated HIV strain leads to very slow immune deterioration 14-18 years after inadvertent infection
2. Reverse Transcriptase (RT)
   1. RNA-dependent DNA polymerase coded by pol gene
   2. Pol (polymerase, RT) gene is expressed as a fusion protein with gag
   3. Occurs by read through of the termination signal or by frame shifting
   4. Gag-pol fusion protein must be processed by the protease
   5. RT is made in 64K (15K RNAse H associated) and 51K forms
3. Envelope (Env) Protein [6]
   1. Translated as Env 160K precursor and cleaved to gp120 and gp41
   2. p120 binds to CD4 (T4) on helper T lymphocytes and other cells and leads to infection
   3. Monocytes/macrophages, dendritic cells, brain microglia also express CD4
   4. Coreceptors on T cells macrophages (CCR5) or CXCR4 (T cells) required for gp120 binding
   5. Final step of viral entry is fusion of viral envelope with cell membrane mediated by gp41
4. p24 is a HIV nuclear protein marker for active viral replication
5. Mechanisms of Evasion Host Immunity [2]
   1. Heavy glycosylation of external glycoprotein which protects neutralization epitopes
   2. Direct targeting of key immune T lymphocytes through CD4 molecule
   3. Integration into host-cell genome so that cells not killed are infected permanently
   4. Potential for virus to mutate and therefore evade host immune system
   5. Viral mutations lead to marked degree of viral diversity, even within one host

C. Receptors / Coreceptors for HIV [6,7,8]

1. Env protein gp120 binds to CD4 surface molecule and coreceptors on human cells
2. Chemokine receptors CCR5 or CXCR4 are coreceptors required for HIV infection [2,4]
   1. HIV cell type preference on env protein sequence and coreceptor use
   2. Changes in HIV env genes change coreceptor preference (macrophage versus T cell)
   3. During evolution of infection, CCR5 tropic virus may mutate into CXCR4-tropic virus
3. CCR5 Tropic HIV [4,12]
   1. CCR5 expression required mainly for macrophage infection, virus called "M-tropic"
   2. CCR5-delta32 mutation can confer resistance to HIV-1 infection [9]
   3. ~50% of long term survivors of HIV are heterozygous for CCR5 deletion
   4. Nearly all transmitted infectious HIV particles are CCR5-tropic
   5. CCR5 tropic HIV is most common circulating form, even with therapy
   6. CCR5 blockers being developed for HIV, show good efficacy, ~1 log viral reduction
4. CXCR4 Tropic HIV [4]
   1. CXCR4 coreceptor is important for infection of T cells ("T-tropic")
   2. Stromal cell-derived factor 1 (SDF-1) is chemokine ligand for CXCR4
   3. Mutant SDF-1 3' allele not associated with altered disease progression rates [9]
   4. CXCR4 tropic strains are less infectious, and occur in ~40% of treated patients
5. Inhibitors of HIV entry through gp120 and CCR5 are approved for human use [4]

D. Disease Stages [11]

1. Retroviral Syndrome (Primary HIV Infection)
   1. Some 40-90% of HIV negative persons contracting HIV develop a flu-like syndrome
   2. This syndrome has been called "retroviral syndrome"
   3. Usual symptoms are fever, fatigue, pharyngitis, weight loss, myalgias, headache, nausea
   4. Lymphadenopathy or night sweats occur in ~50% of intially infected patients
   5. Symptoms tend to resolve over weeks and patients are then asymptomatic
   6. In first 30 days after infection, HIV-1 RNA levels vary widely (4-6 Log Units / mL)
   7. HIV-1 RNA levels decrease over initial 120 days, then increase without treatment
   8. Peak or near peak RNA levels after initial infection do not predict disease progression rate (changes in CD4 counts) [5]
   9. HIV 1 RNA levels should be determined in all HIV infected persons
2. HIV Replication and Immune Response [7,8,11]
   1. Initial infection is followed within weeks by very high serum titers of virus ("burst")
   2. After initial maximum levels are reached, levels drop to an equilibrium level
   3. Early seeding and destruction of gut associated lymphoid tissue (GALT)
   4. Establishment of HIV reservoir with latent component
   5. Induction of cytotoxic T lymphocytes (CTL) within 4 weeks helps control HIV replication
   6. CTL, especially against the env proteins, are important in early control of HIV
   7. CD4+ T cells supporting CTL are also critical
   8. Immune stimulation increases release of HIV-1 RNA and can cause viremia
   9. Humoral (antibody) immunity is not a major determinant of viral control
   10. IL-6, TNFa, TNFß, IL1 stimulate progression of HIV infection
   11. IFNa, IFNß, IL-16 and IL-10 inhibit progression of HIV infection
   12. Hepatitis GB Virus coinfection slows HIV progression associated with production of Th1 cytokines [13] and various pro-inflammatory chemokines [14]
   13. Survival is better in hepatitis GB virus infected HIV patients than in noninfected [59]
3. Reservoirs of HIV [60]
   1. HIV resides in various anatomical "reservoir" sites
   2. Reservoir sites include resting CD4+ T cells, macrophages, follicular dendritic cells
   3. All CD4+ cells (brain microglia, monocytes) are anatomic reservoir sites
4. HIV infection results in progressive elimination of CD4+ helper T cells
   1. Normal persons have CD4 > 500/µL (usually 800-1400/µL)
   2. CD4+ T count is usually used to predict disease presentation and symptoms
   3. CDC Definition of AIDS as CD4 < 200/µL or CD4+ T <14% of total lymphocytes OR
   4. HIV Defining Illness (see below)
5. HIV-Defining Illnesses
   1. Infection: tuberculosis, atypical mycobacteria, fungal infection, CMV retinitis
   2. Pneumonia: Pneumocystis jiroveci, recurrent bacterial pneumonias (in HIV+ persons) [2]
   3. Gastrointestinal: esophageal candidiasis, atypical mycobacterial diarrhea, recurrent salmonella sepsis, cryptosporidia, isospora
   4. Central Nervous System: Cryptococcal Meningitis, Toxoplasma, PML, HIV encephalopathy
   5. Cancers: Invasive Cervical Cancer (Stage II), Kaposi Sarcoma, Non-Hodgkin Lymphoma (NHL)
   6. Wasting Syndrome: weight loss >10% of usual body weight
6. Multivitamin supplements delayed progression of HIV disease in study in Tanzania [42]

E. Initial Evaluation and Monitoring [3]

1. HIV Testing [15,16]
   1. If early HIV (retroviral) syndrome suspected, then HIV RNA in serum should be obtained
   2. ELISA initially - detects antibodies to HIV proteins (home testing available)
   3. OraQuick® and Reveal® rapid HIV-1 Ab screening tests (3-20 minutes on blood) [15]
   4. Oral test (OraSure®) can detect virus in oral mucosal cells
   5. Confirmatory Western Blot and then HIV viral RNA level
   6. Adding nucleic acid amplification to standard HIV testing allows detection of acutely infected individuals who are highly contageous and may be effectively treated [33]
   7. Patient consent is currently required for testing
   8. All persons at risk, particularly pregnant women, should be screened for HIV [53,54,55]
2. Routine History and Physical Exam
   1. Include baseline Mental Status exam (such as mini-mental exam)
   2. Careful skin, lymph node, pulmonary examinations
   3. History of vaccination is critical
   4. HIV+ women should undergo frequent gynecologic evaluations with Pap Smear [17]
   5. Psychosocial - assess patient goals, social supports, alternative therapies
3. Laboratory Studies
   1. CBC with manual differential, CD4 count
   2. Plasma HIV viral load and genotype test for drug resistance
   3. Electrolytes, renal and liver functions, glucose
   4. Creatine kinase, amylase, lipase
   5. Urinalysis
   6. PPD (tuberculosis test) and anergy panel (prognostic as well as prophylactic)
   7. Syphilis - RPR, STS
   8. Hepatitis B (HBV) and C Virus (HCV) Serology
   9. Toxoplasma serology - affects choice of pneumocystis prophylaxis (see below)
   10. Cytomegalovirus (CMV) titer
   11. Consider Varicella Zoster Virus (VZV) serologies
   12. Pap Smear - high risk of invasive cervical cancer with CD4<500/µL in HIV+ persons [10]
   13. Anal screening for HPV, particularly in high risk (anal intercourse) individuals
   14. In women, abnormal Pap smear / gynecologic infection most often leads to evaluation for HIV [17]
   15. Baseline electrocardiography (ECG)
   16. Consider baseline chest radiography
4. Initial Vaccinations in HIV+ Individuals
   1. Diphtheria/tetanus (every 5 years)
   2. Inactivated polio
   3. Measles
   4. Pneumococcus (every 5 years)
   5. HBV
   6. Hepatitis A Virus (HAV)
   7. Haemophilus influenza B (HIB) - optional
   8. Influenza virus (yearly) - effective in HIV+ persons independent of CD4+ count
5. Frequency of Monitoring CD4 Counts and HIV RNA Levels [20]
   1. In general, two baseline CD4 and HIV RNA level counts should be obtained
   2. q6 months for CD4>500/µL AND viral load <10,000/mL
   3. q3 months for CD4 <500/µL OR viral load >>10,000/mL
   4. Delay CD4 counts to >3-4 weeks after an illness
   5. Monitor HIV RNA levels within 1 month therapy initiation or change
6. Intitute Prophylaxis for Opportunistic Infections

F. Prognosis and Progression [20]

1. Plasma HIV RNA levels
   1. Best single predictor of progression prior to ART initiation
   2. Combination of CD4+ T counts with HIV RNA loads is best overall disease prior to ART
   3. Measured HIV RNA loads should also be used to dictate whether to change therapy
   4. Initial plasma HIV RNA levels are lower in women than men, but rate of progression to AIDS is similar [21]
   5. Plasma HIV RNA levels are also the best predictor of heterosexual transmissibility [23]
2. Prognostic Markers
   1. Following antiretroviral therapy initiation, CD4 count >200/µL and viral load <10K/mL associated with good prognosis [24]
   2. Pretreatment CD4 and viral load have no prognostic value in setting of post-treatment levels [24]
   3. CD4+ counts predict risk of opportunistic infection (OI) and overall survival [25]
   4. HCV coinfection slows CD4 recovery and increases HIV progression [26]
   5. HLA-B*35-Px associated with more rapid progression to AIDS than HLA-B*35-PY [27]
   6. These different Major Histocompatibility Complex molecules bind different peptides
   7. Most long term survivors of HIV lack coreceptors for the virus (such as CKR5 and others)
   8. Heterozygosity of host CCR5 coreceptor predicts longer term survival
3. Antiretroviral Therapy (ART) [28,34]
   1. Combination ART reduces viral load and improves survival [34]
   2. ART can permit CD4 increases to normal levels with complete viral suppression [61]
   3. ART reduces morbidity and mortality even in very severe AIDS (CD4<10-15/µL) [29,30]
   4. ART should generally be started at CD4 <350/µL [35] and >200/µL [36]
   5. Three drug ART regimens including 2 nucleoside reverse transcriptase inhibitors (NRTIs) and either a non-nucleoside RTI (NNRTI) or a protease inhibitor are extremely effective [66]
4. In HIV1+ patients with HSV, anti-HSV drug valacyclovir reducede HIV1 RNA levels by 0.53 log10/mL [52]
5. Successful cardiac transplantation in advanced HIV-1 infected patient reported [37]

G. Summary of Organ System Involvement

1. Immune
   1. Progressive loss of CD4 T cells over time
   2. Increased B Cells (mainly Lyb-5+) often with autoantibodies
   3. Increased Globulin (Ig) levels related to B cell dysregulation
   4. Diffuse Lymphadenopathy
   5. Malignant lymphoma (less common) - usually high grade NHL of B-cell type [47]
2. Oropharyngeal (see below)
   1. Fungal Infections: Candidiasis (thrush), Cryptococcosis, Penicillinosis
   2. Viral: HSV, VZV, Epstein Barr Virus (EBV)
   3. Oral hairy leukoplakia (due to EBV)
   4. Gingivitis - usually bacterial, tuberculosis, MAC
   5. Recurrent Aphthous Ulcers - probably autoimmune
   6. Sjogren-like Syndrome - diffuse infiltrative lymphadenopathy (DILS)
   7. Kaposi Sarcoma
   8. NHL
3. Pulmonary (see below)
4. Gastrointestinal (see below)
   1. Biliary Tract Sepsis
   2. Liver Dysfunction (chronic hepatitis)
   3. HCV coinfection with HIV is a poor prognostic factor [26]
   4. ART reduces liver-related mortality in HIV/HCV coinfection [38]
   5. HBV coinfection with HIV-1 increases risk of liver-related mortality, particularly in patients with reduced CD4 counts [58]
   6. Diarrhea (very common) - variety of organisms (see below)
   7. Pancreatic Disorders (uncommon): consider alcoholism; DDI, various other drugs
5. Dermatologic
   1. Pruritic Papular Rash associated with HIV
   2. Kaposi Sarcoma
   3. Drug rashes including Steven's Johnson Syndrome
   4. Various Infections
   5. Psoriasis may appear and/or flare as CD4 count decreases
   6. Seborrheic dermatitis
   7. Eosinophilic folliculitis
6. Renal Disease [40,41]
   1. Focal segmental glomerulosclerosis is classic HIV associated nephropathy
   2. Thrombotic microangiopathic and immune-mediated renal disease can also occur
   3. Interstitial fibrosis then occurs, but changes may reverse with HAART [40]
   4. HIV disease associated with 1-2% of end stage renal disease
   5. Nephrotic syndrome initially with rapid progression to azotemia
   6. Chronic disease may responds to 1mg/kg/d prednisone
   7. ACE inhibitors are also useful and slow progression
   8. Infection prophylaxis should be given if prednisone is used
7. Nervous System
   1. Infections
   2. CNS Lymphoma (NHL) [47]
   3. Dementia and other Psychiatric Disorders
   4. Cauda equina syndromes
   5. Other Neuropathies
8. Anemia [63]
   1. Medication associated
   2. Nutritional deficiency
   3. Opportunistic infection - bone marrow infection
   4. Malignancy - both marrow invasion and erythropoiesis suppression
   5. Progressive HIV infection

H. Opportunistic Infections [43]

1. Most infections now only occur in very late stage HIV
   1. OI's are much less common since introduction of ART []
   2. OI's now uncommon in HIV+ children on ART [19]
2. Bacterial
   1. Pneumonia - bacterial and mycobacterial increased risk, especially with CD4<50/µL [65]
   2. Bacterial diarrhea - including Salmonella, others
   3. Salmonella sepsis
   4. Folliculitis
   5. Mycobacterium tuberculosis - CD4<100/µL
   6. Mycobacterium avium-intracellulare (MAC) - CD4<50/µL
3. Fungal
   1. Candidiasis - CD4<200/µL (esophageal)
   2. Pneumocystis jiroveci (carinii) - CD4<200/µL
   3. Cryptococcus - CD4<50/µL
   4. Histoplasmosis
4. Viral
   1. Recurrent HSV - CD4<50/µL
   2. CMV (retinitis mainly) - CD4<50/µL
   3. Human Herpesvirus 8 (etiologic agent for Kaposi Sarcoma) - CD4<200/µL
   4. High grade Human Papilloma Virus (HPV) - about 1 in 5 HIV+ women over 3 years [45]
   5. HPV also causes anal cancers in HIV+ persons ± anal intercourse [46]
   6. JC Virus (etiologic agent of Progressive Multifocal Leukencephopathy, PML)
5. Protozoan
   1. Cryptosporidia - CD4<100/µL
   2. Microsporidia
   3. Isospora
   4. Toxoplasma - CD4<50/µL
   5. Giardia (severe)
   6. Amoeba (severe)

I. Malignant Disorders [17]

1. Malignancy and HIV
   1. Specific AIDS defining cancers occur at much higher risks in HIV+ than in HIV- persons
   2. AIDS defining cancers include: invasive Cervical Cancer (Stage II), Kaposi Sarcoma, and NHL
   3. Increased risks of many non-AIDS defining cancers (see below) [67]
   4. Significantly increased and similar risk of cancer, including non-AIDS defining types, in HIV/AIDS infected persons compared with organ transplant recipients [61]
2. Elevated Risks of Non-AIDS Defining Cancers [67]
   1. Anal: >43X risk (relative incidence is increasing)
   2. Hodgkin's Lymphoma 10-15X risk [63]
   3. Liver: 7.7X risk
   4. Lung: 3.3X risk
   5. Melanoma: 2.6X risk
   6. Oropharyngeal: 2.6X risk
   7. Leukemia: 2.5X risk
   8. Colorectal: 2.3X risk
   9. Renal 1.8X risk
   10. Risk of prostate cancer was 0.6X that of general population
3. NHL [47,48]
   1. About 300X increased risk versus HIV- persons [63]
   2. Non-CNS and CNS associated NHL, nearly all diffuse B cell tumors
   3. Mainly Epstein Barr Virus (EBV) associated, high grade [59]
   4. Centroblastic (45%), Immunoblastic (13%), Burkitt Type (40%)
4. Cervical and Vulvar Cancer [10]
   1. Increased risk for HPV carriage and early invasive lesions with CD4<500/µL
   2. Much increased risk for frank invasive cervical carcinoma
5. Multiple Myeloma / Plasmacytoma
6. Leiomyosarcoma (in children)
7. Seminoma (possibly)
8. High HIV load and EBV infection increase risk of malignancy in HIV+ children [49]

J. Pulmonary Disease [65]

1. Increased incidence of upper respiratory infections, sinusitis, bronchitis, pneumonia
2. Most common cause for ICU admission of HIV+ patients
3. Pyogenic Bacterial Pneumonia
   1. Rate in HIV+ is ~6X that of normal persons
   2. Rate increased with decreasing CD4 counts and injection drug abuse
   3. Pneumococcus > Staphylococcus ~ Hemophilus > Klebsiella and other gram negatives
   4. Pseudomonas bronchopulmonary infections also increased (CD4 <25/µL)
4. Pneumocystis jiroveci Pneumonia (PJP)
   1. Fungal Organism, previously called P. carinii
   2. Colonizes respiratory tract in all normal humans
   3. All immunosuppressed patients are at increased risk for PCP
   4. Usually acute, diffuse interstitial pneumonia on chest radiograph (CXR)
   5. However, may present with any abnormality on CXR
   6. Induced sputum or bronchoalveolar lavage (BAL) for diagnosis
   7. Prophylaxis for all HIV+ persons with CD4 <200/µL; may discontinue when C
   8. PCP prophylaxis can be discontinue when CD4+ > 200/µL with antiretroviral therapy (ART)
5. Mycobacteria (see below)
   1. Reactivation of Tuberculosis (MTB) occurs at any CD4, especially 200-500/µL
   2. Extrapulmonary / systemic disease with MTB usually occurs with CD4 <150/µL
   3. Disseminated Mycobacterium avium intracellulare infection - CD4 <50/µL
   4. Prophylaxis recommended for CD4<50/µL
6. Fungal Infections
   1. Aspergillus
   2. Cryptococcus
   3. Histoplasma
7. Nocardia asteroides
8. CMV Diffuse Pneumonitis (CD4 <200/µL)
9. Malignancy
   1. High grade NHL common
   2. Kaposi Sarcoma - caused by human herpesvirus 8 (HHV8)
10. Pulmonary Hypertension (PH) []
    1. ~0.5% of patients with HIV develop moderate to severe PH
    2. No correlation between CD4+ T cell count and degree of PH
    3. Pathologic lesions in HIV+ PH are similar to those of other forms of PH
    4. Sildenafil reduces pulmonary pressures and improves exercise tolerance
    5. Caution with use of sildenafil and ART (particularly ritonovir), which can lead to hypotension
11. Lymphoid or Non-specific interstitial pneumonitis

K. Tuberculosis (TB)

1. Increased risk of TB for all HIV+ patients
   1. Both reactivation and primary TB infection increased at any CD4 count
   2. CD4 counts <200µL are particularly prone to active disease
2. Diagnosis
   1. Initial PPD and anergy panel (control) should be done on all new HIV patients
   2. This is important for both prophylaxis / treatment and prognosis
   3. Consider repeating PPD q year until anergic x 2
   4. Many patients with CD4 < 400/µL will be anergic (although test should still be done)
   5. Groups at higher risk for PPD+ are IVDA, black race, previous PPD+, and BCG Vaccine
   6. Induration >4mm in HIV+ patients is considered positive
   7. Rapid nucleic acid based diagnostic tests are now available for respiratory specimens
3. Treatment of Active Infection
   1. Depends on level of multidrug resistance in area
   2. Usually treat initially with 4 agents (INH, RIF, PZA, Ethambutol)
   3. Resistant TB is treated with with streptomycin and/or other active drugs
   4. With standard doses, rifampin and pyrazinamide levels may be low in HIV patients
   5. This correlates with D-xylose malabsorption (but not with presence of diarrhea)
   6. Treatment should be continued at least one year
   7. Pyridoxine 25mg po qd should be given to all patients taking INH
4. Prophylaxis
   1. Given to all HIV+ who are PPD+ or those with CD4 <200/µL and MTB close contact
   2. Should NOT be given to HIV+ patients who are anergic unless exposed to active TB
   3. INH (isoniazid) 300mg po qd with pyridoxine 50mg po qd for one year minimum
   4. Directly observed therapy is often required for HIV+, PPD+, drug abusers
   5. HIV+ persons with PPD+ benefit signficantly from INH prophylaxis
   6. HIV+ patients may be given 600-800mg/day INH
   7. Rifampicin + pyrazinamide for 2 months are as effective as INH for TB prevention in HIV+
5. Drug Interactions
   1. Proease inhibitors and NNRTIs cannot be used with rifampin
   2. Rifabutin can be used with indinavir, nelfinavir, not with saquinavir, ritonavir, NNRTIs
   3. Antiretroviral agents can be used with isoniazid, pyrazinamide, ethambutol

L. Odynophagia and Dysphagia

1. Odynophagia
   1. Pain on swallowing, implies inflammatory process (usually esophagitis)
   2. Esophagitis mainly occurs with very low CD4 counts
   3. Candida - most common cause of odynophagia; infrequent cause of ulceration
   4. HSV and CMV
   5. HIV itself
   6. Idiopathic Ulcerations (~40%) - includes aphthous ulcers
   7. Reflux esophagitis
2. Dysphagia
   1. Difficulty swallowing
   2. Infectious process, as for odynophagia
   3. Neoplastic process: Kaposi's Sarcoma, Lymphoma
3. Evaluation
   1. If oral candidiasis present, then treat (Fluconazole, 100-200mg/day po)
   2. Oral amphotericin B suspension is now available for resistant oral candidiasis
   3. No oral disease, or partial/no improvement strongly suggests that endoscopy be done
   4. Must rule out HSV or CMV
   5. HSV treated with acyclovir
   6. CMV treated with ganciclovir
4. Common Organisms in HIV
   1. Esophagus: C. albicans, CMV, HSV
   2. CMV esophagitis correlates with early mortality
   3. Stomach: CMV, MAI
5. Fungal Prophylaxis
   1. Fluconazole versus clotrimazole troches
   2. Fluconazole more active, more expensive, more side effects
   3. Greatest prevention in patients with <50 CD4+/µL
   4. Usually recommended only in patients with previous fungal disease
   5. High risk of generating resistant organisms with fluconazole prophylaxis
6. Aphthous Ulcers
   1. Unclear etiology in many patients with HIV
   2. May be due to Tumor Necrosis Factor alpha (TNFa) production stimulated by HIV
   3. May respond to topical steroids or oral prednisone (low to moderate levels)
   4. Thalidomide 100-200mg/day may have efficacy in resistant cases
   5. Thalidomide increased HIV RNA ~0.4 log and caused rash and somnolence
   6. Thalidomide must NOT be given to patients at risk for pregnancy

M. Diarrhea

1. Bacteria
   1. Mycobacterium avium complex (MAC)
   2. Salmonella ssp
   3. Campylobacter jejuni
   4. Shigella flexneri
   5. Brachyspira aalborgi (a spirochete)
2. Protozoa
   1. Cryptosporidium
   2. Microsporidium (Enterocytozoon bieneusi, Septata intestinalis and others)
   3. Isospora
   4. Giardia, Entamoeba (especially with history of anal intercourse)
   5. Blastocystis hominis
   6. Cryptosporidia and Isospora more common in underdeveloped countries than USA
   7. Crypto- and microsporidia commonly cause severe diarrhea, malabsorption, wasting
3. Viruses
   1. CMV or HSV
   2. HIV itself (AIDS Enteropathy)
   3. Rotavirus (Australia; uncommon in USA), Adenovirus
   4. Astrovirus and Picobirnavirus may play role
   5. Histoplasma capsulatum
4. Other
   1. Drugs: didanosine, magnesium salts, laxatives, nelfinavir
   2. Small Intestinal Lymphoma (non-Hodgkin)
   3. Kasposi Sarcoma
5. Diagnostic Tests
   1. Fecal Leukocytes (including eosinophils)
   2. Enteric Pathogens Cultures recommended - including MAC isolators
   3. Fungal and Viral Cultures
   4. Protozoal Cultures (Ova and Parasitesm, 3 samples) - with special stains
   5. C. difficile Toxin
   6. Specific Pathogen can be determined in ~75% of patients
   7. Negative Evaluation: Endoscopy ± biopsy; cultures for bacteria, fungus, virus
6. Treatment
   1. Treat infection (standard dosing with prolonged course); stop drug
   2. Opiates: diphenoxylate, Loperamide
   3. Oral rehydration
   4. Microsporidia: may try albendazole, thalidomide, or atovaquone
   5. Metronidzole is highly effective against Brachyspira
   6. Octreotide (Sandostatin®): reduces diarrhea volume in cryptosporidia / microsporidia
   7. Rifabutin and clarithromycin appear to protect against cryptosporidium infection
   8. Isospora is treated well with TMP/SMX DS TID x 10 days; then twice/week x 3 weeks
   9. S. intestinalis may respond well to albendazole
   10. Cryptosporidia: paromomycin, azithromycin, nitazoxanide [56]
7. Treatment of MAC
   1. Therapies of active infection require multiple agents
   2. All regimens should include either clarithromycin 500mg bid or azithromycin 500mg qd
   3. One or more (prefer 2) of the following should be added:
   4. Ethambutol or Rifabutin or Clofazamine or Ciprofloxacin or Amikacin Sulfate
   5. Current standard is clarithromycin + rifabutin + ethambutol unless resistant
8. Intestinal infection (± diarrhea) may lead to drug/food malabsorption

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