.

    Introduction

    • 1 million infected in US (1/3 unaware of diagnosis). 
    • Transmission:
      • Spread through sexual content
      • Contaminated blood (IVDU, occpational, tranfusion)
      • Perinatally
    • Risk Factors:
      • MSM
      • IDU sharing needles
      • Immigrants from countries with high HIV prevalence (African)
      • Sex and drugs (ETOH, ectasy, cocaine)
      • Group Sex
      • Traumatic intercourse (raping)
      • Transfusions before 1985 (consider before 1991)
      • Other STIs
    • Prophylaxis:
      • Pre-Exposure Prophylaxis: In 2012, FDA approved Emtricitabine/Tenofovir Disoproxil Fumarate for pre-exposure prophylaxis.
        • Contraindicated for unknown or positive HIV status (causes resistance)
      • Post-Exposure prophylaxis
        • Standard for occupational exposure, and sometimes sexual.
    • Pathophysiology:
      • HIV is a retrovirus infects CD4 cells (T-helper lymphocytes), replicate, integrade into genome.
        • Descrution of CD4 cells leads to immunocompromised (90% of patients).

    Symp toms:

    • Acute Retroviral Syndrome (ARS) Chronic HIV Symptoms

      96% - Fever

      74% - Lymphadenopathy

      70% - Pharyngitis + Rash

      54% - Myalgia + Arthralgia

      33% - Diarrhea / Headache

      27% - Nausea/Vomiting

      14% - HSM

      12% - Wt loss , thrush, neuro symptoms

      - Lymphadenopathy

      - B-Sx: Fever, Night Sweats / Fatigue / Wt Loss

      - Chronic diarrhea

      - Skin: Seborrheic Dermatitis, Tinea, Onycomycosis

                 Oral aphthous ulcers, Oral hairy leukoplakia, 

                 Gingivitis/periodontitis

      - Neuro: Peripheral Neuropathy

      - Blood: Anemia, Leukopenia, Thrombocytopenia

      - Nephropathy

     

    Acute Retroviral Syndrome

    • Seen in 90% of infected pts, most undiagnosed. 
    • Described as acute symptomatic illness can start days to 2-4w post-exposure.  Accurate Dx not always established.
    • Symptoms last 2-3w, anywhere from simple febrile illness to full-blown mononucleosis-type syndrome.
      • See above.
      • Generally fever, arthralgias, myalgias, headache, rash, pharyngitis, oral and/or genital ulcers.
      • Infection resolves after a few weeks, and is followed by asymptomatic period. 
    • During this phase:
      • Lack of immune response, viral levels very high, VERY INFECTIOUS.
      • Symptoms resolve spontaneously.
      • This is also called the "window period", where seroconversion has not yet happened.
      • Results of HIV antibody testing negative, but viral specific test such as PCR are positive at high levels = establishes dx.
      • Benefit of beginning of antiretroviral therapy (ART) not proved, but theoretical.

     

    Chronic HIV Infection

    • Period of years of symptomatic infection occurs --> depletion of CD4 T-lymphocytes progresses.
    • AIDs
      • Prior to progression patients can get common infections that don't quality as "opportunistic", but prolongued or severe:
        • Recurrent or refractory vaginal candidiasis.
        • Severe oral/genital HSV infection.
        • Herpes zoster infection
        • Pneumococcal pneumonia
      • Diagnosis of AIDS:
        • Diagnosis of AIDS:
           

          • Development of "indicator" opportunistic infections or malignancies
            OR
          • CD4 count drops to < 200 / uL

    Screening

    • Center of Disease Control and Prevention in 2006 - widens testing, reduction of barriers of testing.
    • All 13-64yo pts recommended to be tested at least once (unless prevalence < 0.1% in the region)
      • Some guidelines expand to 75 years.
    • Risk Factors:  (Should undergo annual testing)
      • IVDU and their sex partners
      • Pts who exchange sex for money or drugs
      • Sex partners of HIV infected ppl
      • Men Sex with Men
      • Patients who have had more than one sex partner since last HIV test
    • Also Screen:
      • Pregnant women, early in pregnancy.
    • Now at-home rapid HIV test approved (uses swabs or oral fluid from upper/lower gums for antibodies)
      • All results must be confirmed in office (due to window period), even if negative, repeat in 3 mo.

    Diagnosis

    • Two stage serologic testing:

       

      1. Initial: Enzyme ImmunoAssay (EIA)

           (NEGATIVE EIA = enough to exclude HIV except in window period before seroconversion).

           - If negative, repeat in 6-12w once seroconversion is established.

           - If diagnosis during acute infection required: do quantitative PCR.

          Use of viral load as a routine diagnostic test is discouraged. (poor during low viral load, and $$$).

      2. Confirmatory: Western Blot Assay  (Sn 99.5%, Sp 99.99%)

           - Negative Western Blot = false positive EIA

           - Indeterminate WB Assay = Presence of antibody bands to certain viral antigens

                                                        but insufficient to establish dx.(can happen during actute infection during low Ab levels)

           - Repeated Indeterminate = Cross-reacting antibody (to another antigen).

       

      - Quantitative RNA PCR (Viral Load) - Useful during Acute Retroviral Syndrome, but discouraged as a general diagnostic

                                                                      test. (Poor test when viral load is low duing chronic infection).

       

    • Rapid HIV tests now available in kits (EIA tests)
      • Positive results require standard follow-up confirmatory testing.
    • NEVER appropriate to tell the patient they have HIV based on EIA alone (without confirming with Western Blot).
    • Indications For HIV testing: Symptoms, Opportunistic Infection, severe/recurrent infection (non-opportunistic), TB, HBV, HCV, other STI, hemophilia, high-risk behaviour, persons 13-64 (unless <0.1% prevalence) , known/suspected HIV exposure, sexual assault, patient request, all pregnant women, child born to mother HIV+, occupational exposure, Blood/semen/organ donor.

    Evaluation

    • Complete history (social, sexual), phyisical exam (signs/symptoms of opportunistic infections), counselling (prevention/transmissino).
    • Lab Tests Indicated for new diagnosis:
      • Repeat HIV ab if no documentation
      • Viral resistance testing (NEW recommendtion) - guides ART
      • Viral load (HIV RNA PCR),  CD4 count - Determines stage of Infection
      • Health Status: CBC+Diff, chemistry (incl, creatinine, fasting glucose), Liver (chemistry, enzymes), serum lipids, 
      • Co-Infection: TB skin test or IGRA, Pap test, Toxoplasma serology, Varicella/CMV serology for high risk.
      • Co-Infection: Hep B/C, Syphilis serology +/- other STI

    Treatment

    Prevention of Complications

    • All patients with HIV should get following vaccines: (as indicated for general public)
      • Pneumococcal polysaccharide
      • Hep B vaccine (3 doses) if not immune
      • Annual Influenza
      • Tetanus, Diptheria, Acellular pretussus
      • HepA
      • HPV
      • Meningicoccal
    • AVOID Live Virus Vaccines:
      • MMR
      • Varicella  (studies ongoing for HIV+ and high CD4 counts).
    • All HIV patients need:
    1. Exclude MAC (clinically and negative blood cultures)
    • (prophylaxis not effective in treatment, azithro resistance can emerge).
    1. Tuberculin skin test or IGRA
    • Check TB Skin Test (>5cm = positive) or positive IGRA  = INH 300mg/day x9mo.

    Opportunistic Prophylaxis:

    • Indication Opportunistic Infection Preferred Drug
      CD4 < 200/uL

      Pneumocystis jirovecii

      Candidiasis (oral/esopageal)

      TMP/SMX double-strength OD or 3x/week
      CD4 < 100/uL

      Toxoplasmosis (but need positive serology)

      Cryptococcus (meningitis risk)

      Histoplasma (Not in Canada)

      TMP/SMX, double strenght OD
      CD4 < 50

      Mycobacterium avium complex (MAC)

      CMV

      Azithromycin 1200 mg/week

       (Cover MAC)

      TST > 5mm or
      positive IGRA
      Tuberculosis INH 300 mg/d for 9 months

    Anti-Retroviral Therapy

    • Treatment transformed from uniformly fatal infection into a manageable chronic disease.
    • New Guidelines: Treat all irregardless of CD4 count.  (used to be 350/uL then 500/uL, viral loads etc.)
    • Highly Active Anti-Retroviral Therapy (HAART)
      • Term used initlaly to differentiate  more aggressive multiple drug therapy (from single/double that was standard).
      • But now HAART = ART now. (now standard of care).
    • Baseline resistance testing is standard of care, to guide choice of agents and in treatment failure(suboptimal control of viral load)
      • Need >500 copies/mL of blood for resistance testing.
      • Do not need to stop ART to do repeat resistance testing (need selective pressure).
    • When to initiate treatment?
      • NEW GUIDELINE --> INDICATED FOR ALL PATIENTS UNLESS THERE IS A CONTRAINDICATION
        • Early Treatment Benefit demonstrated, start as early as possible!
        • Previous indications:
          • History of AIDS-definine opportunistic infection
          • Symptomatic HIV or HIV nephropathy
          • CD4 count <500/uL
          • Active co-infection with HepB/C
          • Pregnancy to prevent perinatal transmission
    • Newest drug regimens are published at www.aidsinfo.nih.gov
    • Objective: fully suppress viral replication to prevent development of drug resistance. --> to make viral load = undetectable.
      • Must discuss adherence!!! (difficult!!)
    • Treatment Regimens:
      • At least 3 drugs from at least 2 different classes.
      • Current drug regimen (2014):
        • Two NARTI (Tenofovir, Emtricitabine) + NNRTI (Efaverenz) = once daily combination pill.
        • Combination pill improves adherence and effectiveness.
        • Caution = neural tube defects in pregnancy (avoid in women high risk of pregnancy).  Substitude Efaverenz with integrase inhibitor (Raltegravir) or protease inhibitor (Atazanavir or Duranavir).
          • Protease inhibitors given with small dose of ritonavir (boosts drug levels of protease inhibitors, rather than anti-retroviral itself - inhibits CYP450, improves drug levels, effectiveness, tolerability of others.). 
    • UNDER CONSTRUCTION
      • Category Drug Notes

        NARTI

        (Nucleoside analog reverse

        transcriptase inhibitor

        aka NARTIs)

        Stavudine

        - Causes changes in fat distribution.

        - Can cause mitochondrial toxicity--> fatal lactic acidosis

        - Not used as often anymore.

        Zidovudine - Pregnancy
        Didanosine - lactic acidosis (can be fatal)
        Lamivudine - Pregnancy - newer

        Emtricitabine - Common

        - newer
        Tenofovir - Common - Rare Fanconi syndrome.
        Abacavir  

        NNRTI

        (Nonnucleoside RTI's)

        Efavirenz - Common Neural tube defects in pregnancy, AVOID
        Etravirine  
        Nevirapine  
        Rilpivirine  
        Protease Inhibitors

        Atazanavir

        Duranavir

        Fosamprenavir

        Indinavir

        Lopinavir - Pregnancy

        Nelfinavir

        Ritonavir - Pregnancy

        Saquinavir

        Tipranavir

        Atazanavir - avoid PPI's.

        ALL protease inhibitors - avoid lovastatin and simvastatin

          (HIV on ART = pravastatin is statin of choice).

        Entry Inhibitors

        Enfuvirtide

        Maraviroc

         
        Integrase Inhibitor Raltegravir  

     

    Pregnant Patients

    • HIV testing appropriate for all pregnant women.
    • 1 in 4 chance of acquiring HIV perinatally if ART not given.
      • ART reduces transmission 25% to <2%.
    • Can be transmitted through breast milk, mothers SHOULD NOT breastfeed infants, if alternative is available.
    • Preferred ART:    
      • Zidovudine, lamivudine and lopinavir/ritonavir
        • NOTE: Efavirenz is teratogenic, avoid in pregnancy!
      • After delivery - same indications as non-pregnant adults.

    Treatment Compliations

    1. Metabolic:
      1. Hyperlipidemia / Insulin Resistance
        • Lab Value HIV Infection ART
          Total Cholesterol Decrease Increases
          LDL Decrease Increases
          HDL Decrease Remains decreased
          Triglycerides Increase Remains increased
        • Protease inhibitors are especially associated with hyperlipidemia.
        • Atorvastatin is effective in decreasing hyperlipidemia, however it interacts with protease inhibitor Ritonavir.
          • Start at LOWER doses
        • Insulin resistance develops or worsens in HIV infection.
        • Must measure Fasting Lipids, glucose, HbA1c with every initiation or change in ART.  And needs periodic followup.
      2. Body fat redistribution, lipid dystrophy
        • Changes in body fat distribution -
          • Truncal and visceral fat accumulation.
          • Loss of sucutaneous fat in face and extremities.
        • Decrease fat mobilization by avoiding thymidine analogue reverse transcriptase inhibitors (stavudine, zidovudine).
      3. Mitochondrial toxicity - leading to lactic acidosis.
        • Can be fatal.
        • Decreased with replacement of stavudine, zidovudine, didanosine with lamivudine or emtricitabine and tenofovir.
      4. Osteopenia/ Osteoporosis - Due to HIV infection.
        • DEXA scan only recommended in >50yo  or other risk factors.
      5. CKD - HIV Associated Nephropathy
        • Can be reversed with tx of HIV (if found early).
        • May require transplant/dialysis.
      6. Liver Disease - High prevalence of co-infection with HepB/C
        • Can have regimens against both HIV and HepB.
        • Concurrent HIV / HepC infection --> high risk of progression to liver disease.
    2. Cardiovascular Disease
      • Due to HIV infection as well as ART.
      • SMART studyrandomized pts w/ CD4 > 350/uL to continue ART vs. CD4-cell count guided treatment interruptions.  Pts in treatment interruptions arm had more infections, more cardiovascular disease, and death. (Early termination).
        • Demonstrated that increase in CVD caused by metabolic s/e of treatment is more than offset by risk reduction of what it would be with uncontrolled HIV infection.
        • This increased risk is thought to be due to ongoing inflammation --> increases risk of atherosclerosis.
      • Focus on modifiable CV risk factors: smoking, hyperlipemia, HTN, DMII.
    3. Immune Reconstitution Inflammatory Syndrome (IRIS)
      • With initiation of ART, viral load falls sharply, CD4 counts increase quickly, and immune response is improved.
      • Presence of opportunistic infection that hasn't been previously recognized.
        • Most commonly MAC, TB, or disseminated fungemia.
      • Reconstituted immune system reacts drastically to the high burdens of antigens --> IRIS.
      • This occurs few weeks to few months after ART is initiated.
      • Treatment:
        • CONTINUE treatment.
        • Corticosteroids to moderate excessive inflammation.

     

    Opportunistic Infections

    • Unlikely with CD4 >200 uL (threshold value used to define AIDs).
    •   CD4 Count   Treatment
      Oral Candidiasis CD4 < 200

      - Risk Factors (inhaled corticosteroids, esophageal candidiasis)

        Extension to esophageal candidiasis occurs often in AIDs).

      - Diagnosis: inspection (whitish plaques on oral mucosa).

      - Dysphagia or swallowing issues = esophageal candidiasis.

      Oral Candidiasis: 

        Topical Agents: clotrimazole

        nystatin.

      Esophageal Candidiasis:

        Need systemic agent

         (fluconazole)

      Crytococcal

      Infection

      (Cryptococcal

      meningitis or lung

      Infections)

      Cryptococcal

      Meningitis:

       

      Typically

      CD4 <100

      (can do higher 

      counts)

      - Starts in lung, rarely presents until disseminated
        (meninges  or skin)

      - Subacute/chronic presentation (headaches, changes in
        MS,   systemic sx - fever, nt sweats, wt loss).

      - Focal neuro deficits: cranial nerves common.

      - Diagnosis: culture or cryptococcal antigen test in
        CSF or  serum.

      - Induction therapy with 

        Amphotericin B,

        deoxycholate

       OR lipid formulation of 

        AmpB combined with

        flucytosine.

      - Consolidation therapy:

        fluconazole

      - Monitor ICP!!! high
        mortality,  blindness.

      Pneumocystis
      Jirovecii Pneumonia
      CD4 < 200

      - Dyspnea, dry cough, fever.

      - CXR - diffuse bilateral interstitial/alveolar infiltrates.
      (classically middle-lung fields with cysts, but highly variable)

      - Diagnosis: Stains for organism in sputum or BAL fluid

       

      Treatment: High dose

        TMP/SMX

      - Steroids if arterial

        PaO2 <70mmHg on RA.

        or A-a gradient >35mmHg

      Toxoplasma 

      gondii

      (Encephalitis)

      CD4 < 100

      - Protozoan (intracellular) transmitted with ingestion of

        undercooked meat or exposure to cat feces.

      - Encephalitis

      - Symptoms: fever, headache, focal neuro deficits, seizure

      - Contrast CT or MRI - multiple ring-enhancing lesions

        MRI is modality of choice- high sensitivity (differentiates

        toxo from other infections and CNS lymphoma).

      Treatment: empiric 

         pyrimethamine +

         sulfadiaizine

         OR

         pyrimethamine + clinda

          OR

         TMP/SMX

      - Clinical + radiologic

      response in 1-2w

      Tuberculosis

       

       

      - Likely to be extra-pulmonary

      - Atypical CXR findings, (i.e. not upper lobes)

      - Treatment is complicated

      because interactions with 

      ART meds.

      - Often involves rifabutin

        instead of rifambin.

      Mycobacterium

      Avirum Complex

      (MAC)

      CD4 < 50

      - Presents with fever, sweats, wt loss, lymphadenopathy,

        hepatosplenomegaly, cytopenia.

      - Mycobacterial blood cultures usually positive.

      - Macrolide-based treatment

       (Clarithromycin or 

         Azithromycin)

      Cytomegalovirus

      (CMV)

      CD4 < 50

      - GI involvement: esophageal and colonic ulcers
        (can be anywhere in GI tract)

      - CNS involvement: encephalitis, polyradiculitis

      - CMV Retinitis: most common presentation prior to ART

                    Now only in those patients not responding to ART

                    - Present with floaters, but eventually blindness.

      - URGENT optho exam

      - Ganciclovir, valganciclovir,

        foscarnet

        (esp for CMV retinitis).

      Molluscum

      contaginosum

       

      - Caused by pox virus

      - Dome shaped papules with central umbilication (face/neck)

      - Resolve with ART

      Bacillary

      angiomatosis

       

      - Bartonella infection (most common presentation).

      - Skin lesions (often confused with Kaposi sarcoma).

      bacillaryAngiomatosis.jpg

       

      HHV-8

      Kaposi sarcoma

       

      - Red, purple, brown macules, papules plaques, nodules

        on the skin or mucous membranes. 

      - Primarily in Men-Sex-With-Men group (rare in others)

      kaposiSarcoma.jpeg

       
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